Skip to main content

Advertisement

SpringerLink
Log in

A multi-faceted approach to understanding male infertility: gene mutations, molecular defects and assisted reproductive techniques (ART)

  • Review
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Background

The assisted reproductive techniques aimed to assist infertile couples have their own offspring carry significant risks of passing on molecular defects to next generations.

Results

Novel breakthroughs in gene and protein interactions have been achieved in the field of male infertility using genome-wide proteomics and transcriptomics technologies.

Conclusion

Male Infertility is a complex and multifactorial disorder.

Significance

This review provides a comprehensive, up-to-date evaluation of the multifactorial factors involved in male infertility. These factors need to be first assessed and understood before we can successfully treat male infertility.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Vogt PH. Molecular genetic of human male infertility: from genes to new therapeutic perspectives. Curr Pharm Des. 2004;10:1–29.

    Google Scholar 

  2. Ji G, Long Y, Zhou Y, Huang C, Gu A, Wang X. Common variants in mismatch repair genes associated with increased risk of sperm DNA damage and male infertility. BMC Med. 2012;10:1–10.

    Google Scholar 

  3. De Kretser DM. Male infertility. Lancet. 1997;349:787–90.

    PubMed  Google Scholar 

  4. Dada R, Thilagavathi J, Venkatesh S, Esteves SC, Agarwal A. Genetic testing in male infertility. Open Reprod Sci J. 2011;3:42–56.

    CAS  Google Scholar 

  5. Varghese AC, du Plessis SS, Agarwal A. Male gamete survival at stake: causes and solutions. Reprod Bio Med Online. 2008;17:866–80.

    CAS  Google Scholar 

  6. Matzuk MM, Lamb DJ. Genetic dissection of mammalian fertility pathways. Nat Cell Biol. 2008;4:41–9.

    Google Scholar 

  7. Benoff S, Jacob A, Hurley IR. Male infertility and environmental exposure to lead and cadmium. Hum Reprod. 2000;6:107–21.

    CAS  Google Scholar 

  8. Sharpe RM. Lifestyle and environmental contribution to male infertility. Br Med Bull. 2000;56630–642.

  9. Hosseinzadeh Colagar A, Jorsaraee GA, Tahmasbpour ME. Cigarette smoking and the risk of male infertility. Pakistan Biol Sci. 2007;10(21):3870–4.

    Google Scholar 

  10. Hosseinzadeh Colagar A, Tahmasbpour ME. Ascorbic acid levels in seminal plasma of fertile and idiopathic infertile men: determination and its relationship to sperm quality. J Clin Biochem Nutr. 2009;45:144–9.

    Google Scholar 

  11. Hosseinzadeh Colagar A, Tahmasbpour Marzony E, Chaichi MJ. Zinc levels in seminal plasma are associated with sperm quality in fertile and infertile men. Nutr Res. 2009;29:82–8.

    Google Scholar 

  12. Agarwal A, Allamaneni SSR. Oxidants and antioxidants in human fertility. Middle East Fertil Society J. 2004;9:187–97.

    Google Scholar 

  13. Hosseinzadeh Colagar A, Pouamir M, Tahmasbpour Marzony E, Jorsaraee GA. Relationship between seminal malondialdehyde and sperm parameters quality in the fertile and infertile men. Brazilian Archive Biol Tech. 2009;52(6):1387–92.

    Google Scholar 

  14. Krausz C, Forti G, Mcelreavey K. The Y chromosome and male fertility and infertility. Int J Androl. 2003;26:70–5.

    PubMed  Google Scholar 

  15. Krausz C, Degl’Innocenti S, Nuti F, Morelli A, Felici F, Sansone M, et al. Natural transmission of USP9Y gene mutations: a new perspective on the role of AZFa genes in male fertility. Hum Mol Genet. 2006;15:2673–81.

    CAS  PubMed  Google Scholar 

  16. Walsh TJ, Pera RR, Turek PJ. The genetics of male infertility. Semin Reprod Med. 2009;27:124–36.

    PubMed  Google Scholar 

  17. O'Flynn O’Brien KL, Varghese AC, Agarwal A. The genetic causes of male factor infertility: A review. Fertil Steril. 2010;93:1–12.

    PubMed  Google Scholar 

  18. Asero P, La Vignera S, Lanzafame F. Genetic aspects of male infertility. J Androl Sci. 2010;17:1–16.

    Google Scholar 

  19. Tüttelmann F, Simoni M. Current Recommendations for Genetic Testing in Male Infertility. European Urological Review, 2008; 88-92.

  20. 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.

    CAS  PubMed  Google Scholar 

  21. Maduro MR, Lamb DJ. Understanding the new genetics of male infertility. J Urol. 2002;168:2197–205.

    PubMed  Google Scholar 

  22. Ferlin A, Arredi B, Foresta C. Genetic causes of male infertility. Reprod Toxicol. 2006;22:133–41.

    CAS  PubMed  Google Scholar 

  23. Schiff JD, Palermo GD, Veeck LL, Goldstein M, Rosenwaks Z, Schlegel PN. Success of testicular sperm extraction and intracytoplasmic sperm injection in men with Klinefelter syndrome. J Clin Endocrinol Metab. 2005;90(11):6263–7.

    CAS  PubMed  Google Scholar 

  24. Visootsak J, Graham Jr JM. Klinefelter syndrome and other sex chromosomal aneuploidies. Orphanet J of Rare Diseases. 2006;1:42. Available from: http://www.OJRD.com/content/1/1/42.

    Google Scholar 

  25. Ichioka K, Utsunomiya N, Kohei N, Ueda N, Inoue K, Terai A. Adult onset of declining spermatogenesis in a man with nonmosaic Klinefelter's syndrome. Fertil Steril, 2006; 85(5): 1511 e1-2.

  26. Therman E, Susman M. Human Chromosome: Structure, Behaviour and Effects. New York: Springer-Verlag; 1993.

    Google Scholar 

  27. De Braekeleer M, Dao TN. Cytogenetic studies in male infertility: a review. Hum Reprod. 1991;6:245–50.

    PubMed  Google Scholar 

  28. Ananthapur V, Avvari S, Tella S, Nallari P, Akka J. A Robertsonian Translocation rob (14;15) (q10:q10) in a patient with recurrent abortions: A case report. J Reprod Infertil. 2010;11(3):197–200.

    PubMed  Google Scholar 

  29. Georgiou I, Syrrou M, Pardalidis N, Karakitsios K, Mantzavinos T, Giotitsas ND, et al. Genetic and epigenetic risks of intracytoplasmic sperm injection method. Asian J Androl. 2006;8:643–73.

    PubMed  Google Scholar 

  30. Keymolen K, Van Berkel K, Vorsselmans A, Staessen C, Liebaers L. Pregnancy Outcome in Carriers of Robertsonian Translocations. Am J Med Genet Part A. 2011;155:2381–5.

    Google Scholar 

  31. Gunel M, Cavkaytar S, Ceylaner G, Batioglu S. Azoospermia and cryptorchidism in a male with a de novo reciprocal t(Y;16) translocation. Genet Couns. 2008;19:277–80.

    CAS  PubMed  Google Scholar 

  32. Scriven PN, Flinter FA, Braude PR, Ogivie CM. Robertsonian translocations—reproductive risks and indications for preimplantation gen-etic diagnosis. Hum Reprod. 2001;16:2267–73.

    CAS  PubMed  Google Scholar 

  33. Papadimas J, Goulis DG, Giannouli C, Papanicolaou A, Tarlatzis B, Bontis JN. Ambiguous genitalia, 45, X/46, XY mosaic karyotype, and Y chromosome microdeletions in a 17-year-old man. Fertil Steril. 2001;76:1261–3.

    CAS  PubMed  Google Scholar 

  34. Vogt PH. Human chromosome deletions in Yq11, AZF candidate genes and male infertility: history and update. Mol Hum Reprod. 1998;4:739–44.

    CAS  PubMed  Google Scholar 

  35. 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.

    PubMed  Google Scholar 

  36. Abusheikha N, Lass A, Brisden P. XX males without SRY gene and with infertility. Hum Reprod. 2001;16:717–8.

    CAS  PubMed  Google Scholar 

  37. Vogt PH, Fernandes S. Polymorphic DAZ gene family in poly-morphic structure of AZFc locus: artwork or functional for human sperma-togenesis? Acta Pathol Microbiol Immunol Scand. 2003;111:115–27.

    CAS  Google Scholar 

  38. Foresta C, Ferlin A, Garolla A, Moro E, Pistorello M, Barbaux S, et al. High frequency of well-defined Y-chromosome deletions in idiopathic Sertoli cell-only syndrome. Hum Reprod. 1998;13:302–7.

    CAS  PubMed  Google Scholar 

  39. van der Ven K, Montag M, Peschka B, Leygraaf J, Schwanitz G, Haidl G, et al. Combined cytogenetic and Y chromosome microdeletion screening in males undergoing intracytoplasmic sperm injection. Mol Hum Reprod. 1997;3:699–704.

    PubMed  Google Scholar 

  40. Vogt PH, Edelmann A, Kirsch S, Henegariu O, Hirschmann P, Kiesewetter F, et al. Human Y chromo-some azoospermia factors (AZF) mapped to different subregions in Yq11. Hum Mol Genet. 1991;5:933–43.

    Google Scholar 

  41. Foresta C, Moro E, Ferlin A. Y chromosome microdeletions and alterations of spermatogenesis. Endocr Rev. 2001;22:226–39.

    CAS  PubMed  Google Scholar 

  42. Muslumanoglu MH, Turgut M, Cilingir O, Can C, Ozyurek Y, Artan S. Role of the AZFd locus in spermatogenesis. Fertil Steril. 2005;84:519–22.

    CAS  PubMed  Google Scholar 

  43. Sertic J, Cvitkovic P, Myers A, Saiki RK, Rukavina AS. Genetic Markers of Male Infertility: Y Chromosome Microdeletions and Cystic Fibrosis Transmembrane Conductance Gene Mutations. Croat Med J. 2001;42(4):416–20.

    CAS  PubMed  Google Scholar 

  44. Silber SJ, Alagappan R, Brown LG, Page DC. Y chromosome deletions in azoospermic and severely oligozoospermic men undergoing intracytoplasmic sperm injection after testicular sperm extraction. Hum Re-prod. 1998;13:3332–7.

    CAS  Google Scholar 

  45. Fujisawa M, Shirakawa T, Kanzaki M, Okada H, Arakawa S, Kamidono S. Y-chromosome microdeletion and phenotype in cytogenetically normal men with idiopathic azoospermia. Fertil Steril. 2001;76:491–5.

    CAS  PubMed  Google Scholar 

  46. Selva DM, Hammond GL. Human sex hormone-binding globulin is expressed in testicular germ cells and not in Sertoli cells. Horm Metab Res. 2006;38:230–5.

    CAS  PubMed  Google Scholar 

  47. Selva DM, Hogeveen KN, Seguchi K, Tekpetey F, Hammond GL. A human sex hormone-binding globulin isoform accumulates in the acrosome during spermatogenesis. J Biol Chem. 2002;277:45291–8.

    CAS  PubMed  Google Scholar 

  48. 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.

    CAS  PubMed  Google Scholar 

  49. Vogt PH. Azoospermia factor (AZF) in Yq11: towards a molecular understanding of its function for human male fertility and spermatogenesis. Reprod Biomed Online. 2005;10:81–93.

    CAS  PubMed  Google Scholar 

  50. Galan JJ, Guarducci E, Nuti F, Gonzalez A, Ruiz M, Ruiz A, et al. Molecular analysis of estrogen receptor alpha gene AGATA haplotype and SNP12 in European populations: potential protective effect for cryptorchidism and lack of association with male infertility. Hum Reprod. 2007;22:444–9.

    CAS  PubMed  Google Scholar 

  51. Delbridge ML, Harry JL, Toder R, O'Neill RJ, Ma K, Chandley AC, et al. A human candidate spermatogenesis gene, RBM1, is conserved and amplified on the marsupial Y chromosome. Nat Genet. 1997;15:131–6.

    CAS  PubMed  Google Scholar 

  52. Vogt PH. AZF deletions and Y chromosomal haplogroups: history and update based on sequence. Hum Reprod Update. 2005;11:319–36.

    CAS  PubMed  Google Scholar 

  53. Elliot DJ, Millar MR, Oghene K, Ross A, Kiesewetter F, Pryor J, et al. Expression of RBM in the nuclei of human germ cells is dependent on a critical region of the Y chromosome long arm. Proc Natl Acad Sci. 1997;94:3848–53.

    Google Scholar 

  54. Lahn BT, Tang ZL, Zhou J, Barndt RJ, Parvinen M, Allis CD, et al. Previously uncharacterized histone acetyltransferases implicated in mammalian spermatogenesis. Proc Natl Acad Sci U S A. 2002;99:8707–12.

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Mahanta R, Gogoi A, Chaudhury PNB, Roy S, Bhattacharyya IK, Sharma P, et al. Microdeletions in the Y Chromosome of Infertile Males with Azoospermia, Oligozoospermia and Asthenozoospermia from Assam, India. World Applied Sciences Journal. 2012;17(10):1265–70.

    CAS  Google Scholar 

  56. Vineeth VS, Malini SS. A Journey on Y Chromosomal Genes and Male Infertility. Int J Hum Genet. 2011;11(4):203–15.

    CAS  Google Scholar 

  57. de Carvalho CMB, Zuccherato LW, Fujisawa M, Shirakawa T, Ribeiro-dos-Santos AKC, Santos SEB, et al. Study of AZFc partial deletion gr/gr in fertile and infertile Japanese males. J Hum Genet. 2006;51:794–9.

    CAS  PubMed  Google Scholar 

  58. Krausz C, Quintana-Murci L. McElreaveyK. Prognostic value of Y deletion analysis: what is the clinical prognostic value of Y chromosome microdeletion analysis? Hum Re-prod. 2000;15:1431–4.

    CAS  Google Scholar 

  59. Pinho MJ, Neves R, Costa P, Ferras C, Sousa M, Alves C, et al. Unique t(Y;1)(q12;q12) reciprocal translocation with loss of the heterochromatic region of chromosome 1 in a male with azoospermia due to meiotic arrest: a case report. Hum Reprod. 2005;20:689–96.

    PubMed  Google Scholar 

  60. Zhang J, Qiu SD, Li SB, Zhou DX, Tian H, Huo YW, et al. Novel mutations in ubiquitin-specific protease 26 gene might cause spermatogenesis impairment and male infertility. Asian J Androl. 2007;9(6):809–14.

    CAS  PubMed  Google Scholar 

  61. 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.

    CAS  PubMed  Google Scholar 

  62. Repping S, Skaletsky H, Brown L, van Daalen SK, Korver CM, Pyntikova T, et al. Polymorphism for a 1.6-Mb deletion of the human Y chromosome persists through balance between recurrent mutation and haploid selection. Nat Genet. 2003;35:247–51.

    CAS  PubMed  Google Scholar 

  63. Lardone MC, Parodi DA, Ebensperger M, Penaloza P, Cornejo V, Valdevenito R, et al. AZFc partial deletions in Chilean men with severe sper-matogenic failure. Fertil Steril. 2007;88:1318–26.

    CAS  PubMed  Google Scholar 

  64. 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.

    CAS  PubMed  Google Scholar 

  65. Eloualid A, Rhaissi H, Reguig A, Bounaceur S. El houate B, Abidi O, Charif M, Louanjli N, Chadli E, Barakat A, Bashamboo A, McElreavey K, Rouba H. Association of Spermatogenic Failure with the b2/b3 Partial AZFc Deletion. PLoS ONE. 2012;7(4):e34902.

    CAS  PubMed Central  PubMed  Google Scholar 

  66. Repping S, van Daalen SK, Korver CM, Brown LG, Marszalek JD, Gianotten J, et al. A family of human Y chromosomes has dispersed throughout northern eurasia despite a 1.8-Mb deletion in the azoospermia factor c region. Genomics. 2004;83:1046–52.

    CAS  PubMed  Google Scholar 

  67. de Llanos M, Ballesca JL, Gazquez C, Margarit E, Oliva R. High frequency of gr/gr chromosome Y deletions in consecutive oligospermic ICSI candidates. Hum Reprod. 2005;20:216–20.

    PubMed  Google Scholar 

  68. Tuttelmann F, Rajpert-De Meyts E, Nieschlag E, Simoni M. Gene polymorphisms and male infertility- a meta-analysis and literature review. RBM Online. 2007;15:643–58.

    PubMed  Google Scholar 

  69. Stouffs K, Lissens W, Tournaye H, Haentjens P. What about gr/gr deletions and male infertility? Systematic review and meta-analysis. Hum Reprod Update. 2011;17:197–209.

    CAS  PubMed  Google Scholar 

  70. Ferlin A, Moro E, Garolla A, Foresta C. Human male infertility and Y chromosome deletions: role of the AZF-candidate genes DAZ, RBM and DFFRY. Hum Reprod. 1999;14:1710–6.

    CAS  PubMed  Google Scholar 

  71. Kuo PL, Wang ST, Lin YM, Lin YH, Teng YN, Hsu CC. Expression profiles of the DAZ gene family in human testis with and without spermatogenic failure. Fertil Steril. 2004;81:1034–40.

    CAS  PubMed  Google Scholar 

  72. Teng YN, Lin YM, Lin YH, Tsao SY, Hsu CC, Lin SJ, et al. Association of a single-nucleotide polymorphism of the deleted-in-azoospermia-like gene with susceptibility to spermatogenic failure. J Clin Endocrinol Metab. 2002;87:5258–64.

    CAS  PubMed  Google Scholar 

  73. Fernandes S, Huellen K. Gonc¸alves J, Dukal H, Zeisler J, De Meyts ER, Skakkebaek NE, Habermann B, Krause W, Sousa M et al. High frequency of DAZ1/DAZ2 gene deletions in patients with severe oligo-zoospermia. Mol Hum Reprod. 2002;8:286–98.

    CAS  PubMed  Google Scholar 

  74. Ravel C, Chantot-Bastaraud S, Houate BE, Rouba H, Legendre M, Lorencxo D, et al. Y-chromosome AZFc structural architecture and relationship to male fertility. Fertil Steril. 2009;92:1924–33.

    CAS  PubMed  Google Scholar 

  75. Sadeghi-Nejad H, Farrokhi F. Genetics of azoospermia: current knowledge, clinical implications, and future directions. Part II. Y chromosome microdeletions. Urol J. 2007;4:192–206.

    PubMed  Google Scholar 

  76. Knower KC, Kelly S, Harley VR. Turning on the male-SRY, SOX9 and sex determination in mammals. Cytogenet Genome Res. 2003;101:185–98.

    CAS  PubMed  Google Scholar 

  77. de Carvalho CMB, Santos FR. Human Y-chromosome variation and male dysfunction. J of Mol and Genet Med. 2005;1(2):63–75.

    Google Scholar 

  78. Shahid M, Dhillion VS, Jain N, Hedau S, Diwakar S, Sachdeva P, et al. Two new novel point mutations localized upstream and downstream of the HMG box region of the SRY gene in three Indian 46, XY females with sex reversal and gonadal tumour formation. Mol Hum Reprod. 2004;10:521–6.

    CAS  PubMed  Google Scholar 

  79. Dasari VK, Goharderakhshan RZ, Perinchery G, Li LC, Tanaka Y, Alonzo J, et al. Expression analysis of Y chromosome genes in human prostate cancer. Urol. 2001;165:1335–41.

    CAS  Google Scholar 

  80. Eckardstein S, Cooper TG, Rutscha K, Meschede D, Horst J, Nieschlag E. Seminal plasma characteristics as indicators of cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in men with obstructive azoospermia. Fertil Steril. 2000;73:1226–31.

    Google Scholar 

  81. 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(22):1475–80.

    CAS  PubMed  Google Scholar 

  82. Hiort O, Holterhus PM, Horter T, Schulze W, Kremke B, Bals-Pratsch M, et al. Significance of mutations in the androgen receptor gene in males with idiopathic infertility. J Clin Endocrinol Metab. 2000;85(8):2810–5.

    CAS  PubMed  Google Scholar 

  83. Yong EL, Tut TG, Ghadessy FJ, Prins G, Ratnam SS. Partial androgen insensitivity and correlations with the predicted three dimensional structure of the androgen receptor ligand-binding domain. Mol Cell Endocrinol. 1998;137:41–50.

    CAS  PubMed  Google Scholar 

  84. Mifsud A, Sim CK, Boettger-Tong H, Moreira S, Lamb DJ, Lipshultz LI, et al. Trinucleotide (CAG) repeat polymorphisms in the androgen receptor gene: molecular markers of risk for male infertility. Fertil Steril. 2001;75:275–81.

    CAS  PubMed  Google Scholar 

  85. Mengual L, Oriola J, Ascaso C, Ballesca JL, Oliva R. An Increased CAG Repeat Length in the Androgen Receptor Gene in Azoospermic ICSI Candidates. J Androl. 2003;24:279–84.

    CAS  PubMed  Google Scholar 

  86. Cram DS, Song B, McLachlan RI, Trounson AO. CAG trinucleotide repeats in the androgen receptor gene of infertile men exhibit stable inheritance in female offspring conceived after ICSI. Mol Hum Reprod. 2000;6(9):861–6.

    CAS  PubMed  Google Scholar 

  87. Foresta C, Ferlin A. Role of INSL3 and LGR8 in cryptorchidism and testicular functions. Reprod BioMed Online. 2004;9:294–8.

    CAS  PubMed  Google Scholar 

  88. Mokosch A, Bernecker C, Willenberg HS, Neumann NJ. Kallmann syndrome. Hautarzt. 2011;62:728–30.

    CAS  PubMed  Google Scholar 

  89. Hwang SH, Lee SM, Seo EJ, Choi KU, Park HJ, Park NC, et al. A case of male infertility with a reciprocal translocation t(X;14)(p11.4;p12). Korean J Lab Med. 2007;27(2):139–42.

    CAS  PubMed  Google Scholar 

  90. 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.

    CAS  PubMed  Google Scholar 

  91. Kelly TL, Neaga OR, Schwahn BC, Rozen R, Trazler JM. Infertility in 5, 10 methylenetetrahydrofolate reductase (MTHFR)-deficient male mice is partially alleviated by lifetime dietary betaine supplementation. Biol Reprod. 2005;72:667–77.

    CAS  PubMed  Google Scholar 

  92. Singh AR, Vrtel R, Vodicka R, Dhaifalah I, Konvalinka D, Janikova M, et al. Y Chromosome and Male Infertility. Int J Hum Genet. 2005;5(4):225–35.

    CAS  Google Scholar 

  93. Singh K, Singh SK, Raman R. MTHFR A1298C polymorphism and idiopathic male infertility. J Grad Med. 2010;56:267–9.

    CAS  Google Scholar 

  94. 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.

    CAS  PubMed  Google Scholar 

  95. Rochira V, Granata AR, Madeo B, Zirilli L, Rossi G, Carani C. Estrogens in males: what have we learned in the last 10 years?Asian. J Androl. 2005;7:3–20.

    CAS  Google Scholar 

  96. Sinkevicius KW, Laine M, Lotan TL, Woloszyn K, Richburg JH, Greene GL. Estrogen-dependent and independent estrogen receptor-alpha signaling separately regulate male fertility. Endocrinology. 2009;150:2898–905.

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Ferlin A, Tessari A, Ganz F, Marchina E, Barlati S, Garolla A, et al. Association of partial AZFc region deletions with spermatogenic impairment and male infertility. J Med Genet. 2005;42:209–13.

    CAS  PubMed Central  PubMed  Google Scholar 

  98. Suzuki Y, Sasagawa I, Itoh K. AshidaJ, Muroya K, Ogata T. Estrogen receptor alpha gene polymorphismis associated with idiopathic azoospermia. Fertil Steril. 2002;78:1341–3.

    PubMed  Google Scholar 

  99. Robertson KM, O’Donnell L, Jones ME, Meachem SJ, Boon WC, Fisher CR, et al. Impairment of sperma-togenesis in mice lacking a functional aromatase (cyp 19) gene. Proc Natl Acad Sci. 1999;96:7986–91.

    CAS  PubMed Central  PubMed  Google Scholar 

  100. Guarducci E, Nuti F, Becherini L, Rotondi M, Balercia G, Forti G, et al. Estrogen receptor α promoter polymorphism: stronger estrogen action is coupled with lower sperm count. Hum Reprod. 2006;21:994–1001.

    CAS  PubMed  Google Scholar 

  101. Krege JH, Hodgin JB, Couse JF, Enmark E, Warner M, Mahler JF, Sar M, Korach KS, Gustafsson JA, Smithies O. Generation and reproductive phenotypes of mice lacking estrogen receptor beta.Proc Natl Acad Sci, 1998; 95:15677.

  102. Aschim EL, Giwercman A, Stahl O, Eberhard J, Cwikiel M, Nordenskjold A, et al. The RsaI polymorphism in the estrogen receptor-beta gene is associated with male infertility. J Clin Endocrinol Metab. 2005;90:5343.

    CAS  PubMed  Google Scholar 

  103. Khattri A, Pandey RK, Gupta NJ, Chakravarty B, Deendayal M, Singh L, et al. CA repeat and RsaI polymorphisms in ERbeta gene are not associated with infertility in Indian men. Int J Androl. 2007;32:81–7.

    PubMed  Google Scholar 

  104. Khattri A, Pandey RK, Gupta NJ, Chakravarty B, Deenadayal M, Singh L, et al. Estrogen receptor β gene mutations in Indian infertile men. Mol Hum Reprod. 2009;15:513–20.

    CAS  PubMed  Google Scholar 

  105. Balkan M, Gedik A, Akkoc H, Ay O, Erdal ME, Isi H, et al. FSHR Single Nucleotide Polymorphism Frequencies in Proven Fathers and Infertile Men in Southeast Turkey. J Biomed Biotechnol. 2010;2010:1–5.

    Google Scholar 

  106. Zamudio NM, Chong S, O’Bryan MK. Epigenetic regulation in male germ cells. Reproduction. 2008;136:131–46.

    CAS  PubMed  Google Scholar 

  107. 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.

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Zhang J, Shao XG, Shi YB, Yan L, Wang L, Tian H, et al. Polymorphism of Usp26 correlates with idiopathic male infertility. Zhonghua Nan Ke Xue. 2012;18(2):105–8.

    CAS  PubMed  Google Scholar 

  109. Lee IW, Kuan LC, Lin CH, Pan HA, Hsu CC, Tsai YC, et al. Association of USP26 haplotypes in men in Taiwan, China with severe spermatogenic defect. Asian J Androl. 2008;10:896–904.

    CAS  PubMed  Google Scholar 

  110. Ribarski I, Lehavi O, Yogev L, Hauser R, Bar-Shira Maymon B, Botchan A, et al. USP26 gene variations in fertile and infertile men. Hum Reprod. 2009;24:477–84.

    CAS  PubMed  Google Scholar 

  111. 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.

    CAS  PubMed  Google Scholar 

  112. Cheng Y, Buffone MG, Kouadio M, Goodheart M, Page DC, Gerton GL, Davidson I, Wang PJ. Abnormal Sperm in Mice Lacking the Taf7l Gene. Molecular and Cellular Biology, 2007; 2582-2589.

  113. Falender AE, Freiman RN, Geles KG, Lo KC, Hwang K, Lamb DJ, et al. Maintenance of spermatogenesis requires TAF4b, a gonad-specific subunit of TFIID. Genes Dev. 2005;19:794–803.

    CAS  PubMed Central  PubMed  Google Scholar 

  114. 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.

    CAS  PubMed  Google Scholar 

  115. Kumar DP, Sangeetha N. Mitochondrial DNA mutations and male infertility. Indian J Hum Genet. 2009;15(3):93–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Taylor RW, Turnbull DM. Mitochondrial DNA mutations in human disease. Nat Rev Genet. 2005;6:389–402.

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Alcivar AA, Hake LE, Millette CF, Trasler JM, Hecht NB. Mitochondrial gene expression in male germ cells of the mouse. Dev Biol. 1989;135:263–71.

    CAS  PubMed  Google Scholar 

  118. Solano A, Playan A, Lopez-Perez MJ, Montoya J. Genetic diseases of human mitochondrial DNA. Salud Publica Mex. 2001;43:1–11.

    Google Scholar 

  119. Guney AI, Javadova D, Kırac D, Ulucan K, Koc G, Ergec D, et al. Detection of Y chromosome microdeletions and mitochondrial DNA mutations in male infertility patients. Genet Mol Res. 2012;11:1039–48.

    CAS  PubMed  Google Scholar 

  120. Carra E, Sangiorgi D, Gattuccio F, Rinaldi AM. Male infertility and mitochondrial DNA. Biochem Biophys Res Commun. 2004;322:333–9.

    CAS  PubMed  Google Scholar 

  121. St John JC, Jokhi RP, Barratt CL. Men with oligoasthenoteratozoospermia harbour higher numbers of multiple mitochondrial DNA deletions in their spermatozoa, but individual deletions are not indicative of overall etiology. Mol Hum Reprod. 2001;7:103–11.

    CAS  PubMed  Google Scholar 

  122. May-Panloup P, Chretien MF, Savagner F, Vasseur C, Jean M, Malthiery Y, et al. Increased sperm mitochondrial DNA content in male infertility. Hum Reprod. 2003;18:550–6.

    CAS  PubMed  Google Scholar 

  123. Folgero T, Bertheussen K, Lindal S, Torbergsen T, Oian P. Mitochondrial disease and reduced sperm motility. Hum Reprod. 1993;8:1863–8.

    CAS  PubMed  Google Scholar 

  124. Lestienne P, Reynier P, Chretien MF, Penisson-Besnier I, Malthièry Y, Rohmer V. Oligoasthenospermia associated with multiple mitochondrial DNA rearrangements. Mol Hum Reprod. 1997;3:811–4.

    CAS  PubMed  Google Scholar 

  125. Hoshi K, Kasai T, Ogawa K, Mizuno K, Nagai S, Uchida Y, et al. Relationship between sperm mitochondrial membrane potential, sperm motility, and fertility potential. Asian J Androl. 2002;4:97–103.

    PubMed  Google Scholar 

  126. Kao SH, Chao HT, Wei YH. Multiple deletions of mitochondrial DNA are associated with the decline of motility and fertility of human spermatozoa. Mol Hum Reprod. 1998;4:657–66.

    CAS  PubMed  Google Scholar 

  127. Mundy AJ, Ryder TA, Edmonds DK. Asthenozoospermia and the human sperm mid-piece. Hum Reprod. 1995;10:116–9.

    CAS  PubMed  Google Scholar 

  128. Hecht NB, Liem H, Kleene KC, Distel RJ, Ho SM. Maternal inheritance of the mouse mitochondrial genome is not mediated by a loss or gross alteration of the paternal mitochondrial DNA or by methylation of the oocyte mitochondrial DNA. Dev Biol. 1984;102:452–61.

    CAS  PubMed  Google Scholar 

  129. Wallace DC. Diseases of the mitochondrial DNA. Annu Rev Biochem. 1992;61:1175–212.

    CAS  PubMed  Google Scholar 

  130. Kumar V, Hassan MI, Tomar AK, Kashav T, Nautiyal J, Singh S, et al. Proteomic analysis of heparin-binding proteins fromhuman seminal plasma: a step towards identification of molecular markers of male fertility. J Biosci. 2009;34:899–908.

    CAS  PubMed  Google Scholar 

  131. Folgero T, Torbergsen T, Oian P. The 3243 MELAS mutation in a pedigree with MERRF. Eur Neurol. 1995;35:168–71.

    CAS  PubMed  Google Scholar 

  132. Kao SH, Chao HT, Wei YH. Mitochondrial deoxyribonucleic acid 4977-bp deletion is associated with diminished fertility and motility of human sperm. Biol Reprod. 1995;52:729–36.

    CAS  PubMed  Google Scholar 

  133. Sampson MJ, Decker WK, Beaudet AL, Ruitenbeek W, Armstrong D, Hicks MJ, et al. Immotile sperm and infertility in mice lacking mitochondrial voltage-dependent anion channel type 3. J Biol Chem. 2001;276:39206–12.

    CAS  PubMed  Google Scholar 

  134. Holyoake AJ, Sin IL, Benny PS, Sin FY. Association of a novel human mtDNA ATPase6 mutation with immature sperm cells. Andrologia. 1999;31:339–45.

    CAS  PubMed  Google Scholar 

  135. O’Connell M, McClure N, Lewis SE. A comparison of mitochondrial and nuclear DNA status in testicular sperm from fertile men and those with obstructive azoospermia. Hum Reprod. 2002;17:1571–7.

    PubMed  Google Scholar 

  136. Hosseinzadeh Colagar A, Karimi F. large scale deletions of the mitochondrial DNA in an asthenoterato and oligoasthenoterato-spermic men. Mitochondrial DNA. 2013. doi:10.3109/19401736.2013.796512.

    PubMed  Google Scholar 

  137. St John JC, Jokhi RP, Barratt CLR. The impact of mitochondrial genetics on male infertility. Int J Androl. 2005;28:65–73.

    CAS  PubMed  Google Scholar 

  138. Kumar R, Bhat A, Bamezai RN, Shamsi MB, Kumar R, Gupta NP, et al. Necessity of nuclear and mitochondrial genome analysis prior to ART/ICSI. Indian J Biochem Biophys. 2007;44:437–42.

    CAS  PubMed  Google Scholar 

  139. Lambard S, Galeraud-Denis I, Martin G, Levy R, Chocat A, Carreau S. Analysis and significance of mRNA in human ejaculated sperm from normozoospermic donors: relationship to sperm motility and capacitation. Mol Hum Reprod. 2004;10:535–41.

    CAS  PubMed  Google Scholar 

  140. Kumar R, Venkatesh S, Kumar M, Tanwar M, Shasmsi MB, Kumar R, et al. Oxidative stress and sperm mitochondrial DNA mutation in idiopathic oligoasthenozoospermic men. Indian J Biochem Biophys. 2009;46:172–7.

    CAS  PubMed  Google Scholar 

  141. Thangaraj K, Joshi MB, Reddy AG, Rasalkar AA, Singh L. Sperm mitochondrial mutations as a cause of low sperm motility. J Androl. 2003;24:388–92.

    PubMed  Google Scholar 

  142. Spiropoulos J, Turnbull DM, Chinnery PF. Can mitochondrial DNA mutations cause sperm dysfunction? Mol Hum Reprod. 2002;8:719–21.

    CAS  PubMed  Google Scholar 

  143. Khosronezhad N, Hosseinzadeh Colagar A, Jorsarayi SGA. T26248G-transversion mutation in exon7 of the putative methyltransferase Nsun7 gene causes a change in protein folding associated with reduced sperm motility in asthenospermia men. Reprod Fertil and Dev. 2013. doi:10.1071/RD13371.

    Google Scholar 

  144. 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. Nature Genet. 2001;29:261–2.

    CAS  PubMed  Google Scholar 

  145. Chen SS, Chang LS, Chen HW, Wei YH. Polymorphisms of glutathione S-transferase M1 and male infertility in Taiwanese patients with varicocele. Hum Reprod. 2002;17:718–25.

    CAS  PubMed  Google Scholar 

  146. St John JC, Sakkas D, Barrat CLR. A role for mitochondrial DNA in sperm survival. J Androl. 2000;21:189–99.

    CAS  PubMed  Google Scholar 

  147. Shamsi MB, Kumar R, Bhatt A, Bamezai RNK, Kumar R, Gupta NP, et al. Mitochondrial DNA Mutations in etiopathogenesis of male infertility. Indian J Urol. 2008;24(2):150–4.

    PubMed Central  PubMed  Google Scholar 

  148. Rajender S, Avery K, Agarwal A. Epigenetics, spermatogenesis and male infertility. Mutat Res. 2011;727:62–71.

    CAS  PubMed  Google Scholar 

  149. Rajender S, Agarwal A. Aberrant epigenetic modifications in male infertility. Open Reprod Sci J. 2011;3:57–64.

    CAS  Google Scholar 

  150. Dada R, Kumar M, Jesudasan R, Fernández LJ, Gosalvez J, Agarwal A. Epigenetics and its role in male infertility. J Assist Reprod Genet. 2012. doi:10.1007/s10815-012-9715-0.

    Google Scholar 

  151. Biermann K, Steger K. Epigenetics in male germ cells. J Androl. 2007;28:466–80.

    CAS  PubMed  Google Scholar 

  152. Houshdaran S, Cortessis VK, Siegmund K, Yang A, Laird PW, Sokol RZ. Widespread epigenetic abnormalities suggest a broad DNA methylation erasure defect in abnormal human sperm. PLoS ONE. 2007;2:e1289.

    PubMed Central  PubMed  Google Scholar 

  153. Khazamipour N, Noruzinia M, Fatehmanesh P, Keyhanee M, Pujol P. MTHFR promoter hypermethylation in testicular biopsies of patients with non-obstructive azoospermia: the role of epigenetics in male infertility. Hum Reprod. 2009;24:2361–4.

    CAS  PubMed  Google Scholar 

  154. Wu W, Shen O, Qin Y, Niu X, Lu C, Xia Y, et al. Idiopathic male infertility is strongly associated with aberrant promoter methylation of methylenetetrahydrofolate reductase (MTHFR). PLoS ONE. 2010;5:e13884.

    PubMed Central  PubMed  Google Scholar 

  155. 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;94:1728–33.

    CAS  PubMed  Google Scholar 

  156. Poplinski A, Tuttelmann F, Kanber D, Horsthemke B, Gromoll J. Idiopathic male infertility is strongly associated with aberrant methylation of MEST and IGF2/H19 ICR1. Int J Androl. 2010;33:642–9.

    CAS  PubMed  Google Scholar 

  157. Boissonnas CC, Abdalaoui HE, Haelewyn V, Fauque P, Dupont JM, Gut I, et al. Specific epigenetic alterations of IGF2-H19 locus in spermatozoa from infertile men. Eur J Hum Genet. 2010;18:73–80.

    PubMed Central  PubMed  Google Scholar 

  158. Baarends WM, Wassenaar E, van der Laan R, Hoogerbrugge J, Sleddens-Linkels E, Hoeijmakers JH, et al. Silencing of unpaired chromatin and histone H2A ubiquitination in mammalian meiosis. Mol Cell Biol. 2005;25:1041–53.

    CAS  PubMed Central  PubMed  Google Scholar 

  159. Okada Y, Scott G, Ray MK, Mishina Y, Zhang Y. Histone demethylase JHDM2A is critical for Tnp1 and Prm1 transcription and spermatogenesis. Nature. 2007;450:119–23.

    CAS  PubMed  Google Scholar 

  160. Miller D, Brinkworth M, Iles D. Paternal DNA packaging in spermatozoa: more than the sum of its parts? DNA, histones, protamines and epigenetics. Reproduction. 2010;139:287–301.

    CAS  PubMed  Google Scholar 

  161. Oliva R. Protamines and male infertility. Hum Reprod Update. 2006;12:417–35.

    CAS  PubMed  Google Scholar 

  162. Oliva R, Bazett-Jones D, Mezquita C, Dixon GH. Factors affecting nucleosome disassemble by protamines ‘in vitro’. Histone hyperacetylation and chromatin structure, time dependence, and the size of the sperm nuclear proteins. J Biol Chem. 1987;262:17016–25.

    CAS  PubMed  Google Scholar 

  163. Oliva R, Dixon GH. Vertebrate protamine genes and the histone-to-protamine replacement reaction. Prog Nucleic Acid Res Mol Biol. 1991;40:25–94.

    CAS  PubMed  Google Scholar 

  164. Wu JY, Means AR. Ca2+/calmodulin-dependent protein kinase IV is expressed in spermatids and targeted to chromatin and the nuclear matrix. J Biol Chem. 2000;275:7994–9.

    CAS  PubMed  Google Scholar 

  165. Oliva R, Mezquita C. Histone H4 hyperacetylation and rapid turnover of acetyl groups in transcriptionally inactive rooster testis spermatids. Nucleic Acids Res. 1982;10:8049–59.

    CAS  PubMed Central  PubMed  Google Scholar 

  166. Torregrosa N, Dominguez-Fandos D, Camejo MI, Shirley CR, Meistrich ML, Ballesca JL, et al. Protamine 2 precursors, protamine 1/protamine 2 ratio, DNA integrity and other sperm parameters in infertile patients. Hum Reprod. 2008;21:2084–9.

    Google Scholar 

  167. Aoki VW, Liu L, Carrell DT. Identification and evaluation of a novel sperm protamine abnormality in a population of infertile males. Hum Reprod. 2005;20:1298–306.

    CAS  PubMed  Google Scholar 

  168. Faure AK, Pivot-Pajot C, Kerjean A, Hazzouri M, Pelletier R, Peoc’h M, et al. Misregulation of histone acetylation in Sertoli cell-only syndrome and testicular cancer. Mol Hum Reprod. 2003;9:757–63.

    CAS  PubMed  Google Scholar 

  169. Sonnack V, Failing K, Bergmann M, Steger K. Expression of hyperacetylated histone H4 during normal and impaired human spermatogenesis. Andrologia. 2002;34:384–90.

    CAS  PubMed  Google Scholar 

  170. Steilmann C, Cavalcanti MCO, Bartkuhn M, Pons-Kuhnemann J, Schuppe H, Weidner W, et al. The interaction of modified histones with the bromodomain testis-specific (BRDT) gene and its mRNA level in sperm of fertile donors and subfertile men. Reproduction. 2010;140:435–43.

    CAS  PubMed  Google Scholar 

  171. Kobayashi H, Sato A, Otsu E, Hiura H, Tomatsu C, Utsunomiya T, et al. Aberrant DNA methylation of imprinted loci in sperm from oligospermic patients. Hum Mol Genet. 2007;16:2542–51.

    CAS  PubMed  Google Scholar 

  172. Ostermeier GC, Miller D, Huntriss JD, Diamond MP, Krawetz SA. Reproductive biology: delivering spermatozoan RNA to the oocyte. Nature. 2004;429:154.

    CAS  PubMed  Google Scholar 

  173. Li C, Zhou X. Gene transcripts in spermatozoa: Markers of male infertility. Clin Chim Acta. 2012;413:1035–8.

    CAS  PubMed  Google Scholar 

  174. Li C, Zheng L, Wang C, Zhou X. Absence of nerve growth factor and comparison of tyrosine kinase receptor A levels in mature spermatozoa from oligoasthenozoospermic, asthenozoospermic and fertile men. Clin Chim Acta. 2010;411:1482–6.

    CAS  PubMed  Google Scholar 

  175. Cai ZM, Gui YT. GuoX, Zhang LB, Wang H, Yu J. Low expression of glycoprotein subunit 130 in ejaculated spermatozoa from asthenozoospermic men. J Androl. 2006;27:645–52.

    CAS  PubMed  Google Scholar 

  176. Guo X, Gui YT, Tang AF, Lu LH, Gao X, Cai ZM. Differential expression of VASA gene in ejaculated spermatozoa from normozoospermic men and patients with oligozoospermia. Asian J Androl. 2007;9:339–44.

    CAS  PubMed  Google Scholar 

  177. Papaioanou MD, Nef S. MicroRNAs in the testis: building up male fertility. J Andeol. 2010;31:26–33.

    Google Scholar 

  178. Krawetz SA, Kruger A, Lalancette C, Tagett R, Anton E, Draghici S, et al. A survey of small RNAs in human sperm. Hum Reprod. 2011;26:3401–12.

    CAS  PubMed Central  PubMed  Google Scholar 

  179. Esquela-Kerscher A, Slack FJ. Oncomirs- microRNAs with a role in cancer. Nat Rev Cancer. 2006;6:259–69.

    CAS  PubMed  Google Scholar 

  180. Bouhallier F, Allioli N, Lavial F, Chalmel F, Perrard M, Durand P, et al. Role of miR-34c microRNA in the late steps of spermatogenesis. RNA. 2010;16:720–31.

    CAS  PubMed Central  PubMed  Google Scholar 

  181. Belleannee C, Calvo E, Thimon V, Cyr DG, Legare C, Garneau L, et al. Role of MicroRNAs in Controlling Gene Expression in Different Segments of the Human Epididymis. PLoS ONE. 2012;7:1–13. e34996.

    Google Scholar 

  182. Bjork JK, Sandqvist A, Elsing AN, Kotaja N, Sistonen L. miR-18, a member of Oncomir-1, targets heat shock transcription factor 2 in spermatogenesis. Development. 2010;137:3177–84.

    CAS  PubMed  Google Scholar 

  183. Barad O, Meiri E, Avniel A, Aharonov R, Barzilai A. B entwich I, E inav U, Gilad S, Hurban P, Karov Y, et al. MicroRNA expression detected by oligonucleotide microarrays: system establishment and expression profiling in human tissues. Genome Res. 2004;14:2486–94.

    CAS  PubMed Central  PubMed  Google Scholar 

  184. Yu ZR, Raabe T, Hecht NB. MicroRNA Mirn122a reduces expression of the posttranscriptionally regulated germ cell transition protein 2 (Tnp2) messenger RNA (mRNA) by mRNA cleavage. Biol Reprod. 2005;73:427–33.

    CAS  PubMed  Google Scholar 

  185. Yu Z, Raabe T, Hecht NB. MicroRNA Mirn122a reduces expression of the posttranscriptionally regulated germ cell transi-tion protein 2 (Tnp2) messenger RNA (mRNA) by mRNA cleavage. Biol Reprod. 2005;73:427–33.

    CAS  PubMed  Google Scholar 

  186. Novotny GW, Sonne SB, Nielsen JE, Jonstrup SP, Hansen MA, Skakkebaek NE, Rajpert-De Meyts E, Kjems J, Leffers H. Translational repression of E2F1 mRNA in carcinoma in situ and normal testis correlates with expression of the miR-17-92 cluster. Cell Death and Differentiation, 2007; 14879–882.

  187. Govindaraju A, Uzun A, Robertson L, Atli MO, Kaya A, Topper E, et al. Dynamics of microRNAs in bull spermatozoa. Reprod Biol Endocrinol. 2012;10(82):1–10.

    Google Scholar 

  188. Yan N, Lu Y, Sun H, Tao D, Zhang S, Liu W, et al. A microarray for microRNA profiling in mouse testis tissues. Reproduction. 2007;134:73–9.

    CAS  PubMed  Google Scholar 

  189. Lian C, Sun B, Niu S, Yang R, Liu B, Lu C, et al. A comparative profile of the microRNA transcriptome in immature and mature porcine testes using Solexa deep sequencing. FEBS J. 2012;279:964–75.

    CAS  PubMed  Google Scholar 

  190. Voorhoeve PM, le Sage C, Schrier M, Gillis AJ, Stoop H, Nagel R, et al. D rost J, G riekspoor A et al. A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. Adv Exp Med Biol. 2007;604:17–46.

    PubMed  Google Scholar 

  191. Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, et al. Microarray analysis shows that some microRNAs down-regulate large numbers of target mRNAs. Nature. 2005;433:769–73.

    CAS  PubMed  Google Scholar 

  192. Sun W, Julie Li YS, Huang HD, Shyy JY, Chien S. MicroRNA: a master regulator of cellular processes for bioengi-neering systems. Annu Rev Biomed Eng. 2010;12:1–27.

    CAS  PubMed  Google Scholar 

  193. Hayashi K, Chuva de Sousa Lopes SM, Kaneda M, Tang F, Hajkova P, Lao K, O’Carroll D, Das PP, Tarakhovsky A, Miska EA, Surani MA. MicroRNA biogenesis is required for mouse primordial germ cell development and spermatogenesis. PLoS One, 2008; 3:e1738.

  194. Papaioannou MD, Pitetti JL, Ro S, Park C, Aubry F, Schaad O, et al. Sertoli cell DICER1 is essential for spermatogenesis in mice. Dev Biol. 2009;326:250–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  195. Romero Y, Meikar O, Papaioannou MD, Conne B, Grey C, Weier M, et al. Dicer1 Depletion in Male Germ Cells Leads to Infertility Due to Cumulative Meiotic and Spermiogenic Defects. PLoS ONE. 2011;6:e25241.

    CAS  PubMed Central  PubMed  Google Scholar 

  196. Qin Y, Xia Y, Wu W, Han X, Lu C, Ji G, et al. Genetic variants in microRNA biogenesis pathway genes are associated with semen quality in a Han-Chinese population. Reprod BioMed Online. 2012;24:454–61.

    CAS  PubMed  Google Scholar 

  197. Zhang C, Wang C, Chen X, Yang C, Li K, Wang J, et al. Expression profile of microRNAs in serum: a fingerprint for esophageal squamous cell carcinoma. Clin Chem. 2010;56:1871–9.

    CAS  PubMed  Google Scholar 

  198. Huang S, Li H, Ding X, Xiong C. Presence and characterization of cell-free seminal RNA in healthy individuals: implications for noninvasive disease diagnosis and gene expression studies of the male reproductive system. Clin Chem. 2009;55:1967–76.

    CAS  PubMed  Google Scholar 

  199. Wang C, Yang C, Chen X, Yao B, Yang C, Zhu C, et al. Altered Profile of Seminal Plasma MicroRNAs in the Molecular Diagnosis of Male Infertility. Clin Chem. 2011;57:1722–31.

    CAS  PubMed  Google Scholar 

  200. Girard A, Sachidanandam R, Hannon GJ, Carmell MA. A germline-specific class of small RNAs binds mammalian Piwi proteins. Nature. 2006;442:199–202.

    PubMed  Google Scholar 

  201. Klattenhoff C, Theurkauf W. Biogenesis and germline functions of piRNAs. Development, 135: 3–9.

  202. He Z, Kokkinaki M, Pant D, Gallicano GI, Dym M. Small RNA molecules in the regulation of spermatogenesis. Reproduction. 2009;137:901–11.

    CAS  PubMed  Google Scholar 

  203. Kuramochi-Miyagawa S. K imura T, Ijiri TW, Isobe T, Asada N, Fujita Y, Ikawa M, Iwai N, Okabe M, Deng W et al. Mili, a mammalian member of piwi family gene, is essential for spermatogenesis. Development. 2004;131:839–49.

    CAS  PubMed  Google Scholar 

  204. Carmell MA, Girard A. van de K ant HJ, Bourchis D, Bestor TH, de Rooij DG, Hannon GJ. MIWI2 is essential for spermatogenesis and repression of transposons in the mouse male germline. Dev Cell. 2006;12:503–14.

    Google Scholar 

  205. Deng W, Lin H. miwi, a murine homolog of piwi, encodes a cytoplasmic protein essential for spermatogenesis. Dev Cell. 2002;2:819–30.

    CAS  PubMed  Google Scholar 

  206. Xu M, You Y, Hunsicker P, Hori T, Small C, Griswold MD, et al. Mice deficient for a small cluster of Piwi-interacting RNAs implicate Piwi-interacting RNAs in transposon control. Biol Reprod. 2008;79(1):51–7.

    CAS  PubMed  Google Scholar 

  207. du Plessis SS, Kashou AH, Benjamin DJ, Yadav SP, Agarwal A. Proteomics: a subcellular look at spermatozoa. Reprod Biol Endocrinol. 2011;9(36):1–12.

    Google Scholar 

  208. Aitken RJ, Baker MA. The role of proteomics in understanding sperm cell biology. Int J Androl. 2008;31:295–302.

    CAS  PubMed  Google Scholar 

  209. Caron C, Govin J, Rousseaux S, Khochbin S. How to pack the genome for a safe trip. Prog Mol Subcell Biol. 2005;38:65–89.

    CAS  PubMed  Google Scholar 

  210. Sassone-Corsi P. Unique chromatin remodeling and transcriptional regulation in spermatogenesis. Science. 2002;296:2176–8.

    CAS  PubMed  Google Scholar 

  211. Li HY, Zhang H. Proteome analysis for profiling infertility markers in male mouse sperm after carbon ion radiation. Toxicol. 2013;306(5):85–92.

    CAS  Google Scholar 

  212. Sharma R, Agarwal A, Mohanty G, Jesudasan R, Gopalan B, Willard B, et al. Functional proteomic analysis of seminal plasma proteins in men with various semen parameters. Reprod Biol Endocrinol. 2013;11:11–38.

    Google Scholar 

  213. Milardi D, Grande G, Vincenzoni F, Messana I, Pontecorvi A, De Marinis L, et al. Proteomic approach in the identification of fertility pattern in seminal plasma of fertile men. Fertil Steril. 2012;97:67–73.

    CAS  PubMed  Google Scholar 

  214. Siva AB, Kameshwari DB, Singh V, Pavani K, Sundaram CS, Rangaraj N, et al. Proteomics-based study on asthenozoospermia: differential expression of proteasome alpha complex. Mol Hum Reprod. 2010;16:452–62.

    CAS  PubMed  Google Scholar 

  215. Kashou AH, Benjamin DJ, Agarwal A, du Plessis SS. The Advent of Sperm Proteomics has Arrived. Open Reprod Sci J. 2011;3:92–7.

    CAS  Google Scholar 

  216. Sharma A, Agarwal A, Mohanty G, Hamada AJ, Gopalan B, Willard B, et al. Proteomic analysis of human spermatozoa proteins with oxidative stress. Reproductive Biology and Endocrinology. 2013;11(48):1–18.

    Google Scholar 

  217. Thacker S, Yadav SP, Sharma RK, Kashou A, Willard B, Zhang D, et al. Evaluation of Sperm Proteins in Infertile Men: A Proteomic Approach. Fertil Steril. 2011;95:2745–8.

    CAS  PubMed  Google Scholar 

  218. 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.

    CAS  PubMed  Google Scholar 

  219. Zhao L, Burkin HR, Shi X, Li L, Reim K, Miller DJ. Complexin I is required for mammalian sperm acrosomal exocytosis. Dev Biol. 2007;309:236–44.

    CAS  PubMed Central  PubMed  Google Scholar 

  220. de Mateo S, Martinez-Heredia J, Estanyol JM, Dominguez-Fandos D, Vidal-Taboada JM, Ballesca JL, et al. Marked correlations in protein expression identified by proteomic analysis of human spermatozoa. Proteomics. 2007;7:4264–77.

    PubMed  Google Scholar 

  221. Agarwal A. Relationship between oxidative stress, varicocele and infertility: a meta-analysis. Reprod BioMed Online. 2006;12:630–3.

    CAS  PubMed  Google Scholar 

  222. Vaidya D. The hormonal assessment of the infertile male. In: A Publication of the Hope Infertility Clinic. 2006; Available at: education. vsnl.com/hic/hic.html.

  223. Askienazy-Elbhar M. Male genital tract infection: the point of view of the bacteriologist. Gynecol Obstet Fertil. 2005;33(9):691–7.

    CAS  PubMed  Google Scholar 

  224. Peterson CM. Human reproduction: clinical, pathologic and pharmacologic correlations. In: Human Reproduction. 2006; Available at: library.med.utah.edu/kw/human_reprod/seminars/seminar2B.html.

  225. Collins JA, Burrows EA, Yeo J, YoungLai EV. Frequency and predictive value of antisperm antibodies among infertile couples. Hum Reprod. 1993;8:592–8.

    CAS  PubMed  Google Scholar 

  226. Ambasudhan R, Singh K, Agarwal JK, Singh SK, Khanna A, Sah RK, et al. Idiopathic cases of male infertility from a region in India show low incidence of Y-chromosome microdeletions. J Biosci. 2003;28:605–12.

    CAS  PubMed  Google Scholar 

  227. Hwang SK, Makita Y, Kurahashi H, Cho YW, Hirose S. Autosomal dominant nocturnal frontal lobe epilepsy: a genotypic comparative study of Japanese and Korean families carrying the CHRNA4 Ser284Leu mutation. J Hum Genet. 2011;56:609–12.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biology, Islamic Azad University, Sari, Iran

    Eisa Tahmasbpour

  2. Case Western Reserve University, 44106, Cleveland, OH, USA

    Dheepa Balasubramanian

  3. Center for Reproductive Medicine, Cleveland Clinic, 44195, Cleveland, OH, USA

    Ashok Agarwal

Authors
  1. Eisa Tahmasbpour
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dheepa Balasubramanian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ashok Agarwal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ashok Agarwal.

Additional information

Eisa Tahmasbpour and Dheepa Balasubramanian have contributed equally

Capsule This review reports the genetic, molecular and phenotypic factors that greatly facilitate the understanding and treatment of a multi-factorial disorder, Male infertility.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tahmasbpour, E., Balasubramanian, D. & Agarwal, A. A multi-faceted approach to understanding male infertility: gene mutations, molecular defects and assisted reproductive techniques (ART). J Assist Reprod Genet 31, 1115–1137 (2014). https://doi.org/10.1007/s10815-014-0280-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10815-014-0280-6

Keywords

Search

Navigation