Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The biology of infertility: research advances and clinical challenges

Abstract

Reproduction is required for the survival of all mammalian species, and thousands of essential 'sex' genes are conserved through evolution. Basic research helps to define these genes and the mechanisms responsible for the development, function and regulation of the male and female reproductive systems. However, many infertile couples continue to be labeled with the diagnosis of idiopathic infertility or given descriptive diagnoses that do not provide a cause for their defect. For other individuals with a known etiology, effective cures are lacking, although their infertility is often bypassed with assisted reproductive technologies (ART), some accompanied by safety or ethical concerns. Certainly, progress in the field of reproduction has been realized in the twenty-first century with advances in the understanding of the regulation of fertility, with the production of over 400 mutant mouse models with a reproductive phenotype and with the promise of regenerative gonadal stem cells. Indeed, the past six years have witnessed a virtual explosion in the identification of gene mutations or polymorphisms that cause or are linked to human infertility. Translation of these findings to the clinic remains slow, however, as do new methods to diagnose and treat infertile couples. Additionally, new approaches to contraception remain elusive. Nevertheless, the basic and clinical advances in the understanding of the molecular controls of reproduction are impressive and will ultimately improve patient care.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Simple molecular pathway for sex determination in the mammalian gonads.
Figure 2: Sex differentiation in humans.
Figure 3: Neuroendocrine control of pituitary and gonadal function.
Figure 4: Genetic dissection of female fertility pathways in mice.
Figure 5: Mouse models of male reproductive defects provide new insights into the causes of male infertility.

Similar content being viewed by others

Michael L. Eisenberg, Sandro C. Esteves, … Yu-Sheng Cheng

References

  1. Matzuk, M.M. & Lamb, D.J. Genetic dissection of mammalian fertility pathways. Nat. Med. 8, S1, S41–S49 (2002).

    Google Scholar 

  2. Ohinata, Y. et al. Blimp1 is a critical determinant of the germ cell lineage in mice. Nature 436, 207–213 (2005).

    Google Scholar 

  3. Hayashi, K., de Sousa Lopes, S.M. & Surani, M.A. Germ cell specification in mice. Science 316, 394–396 (2007).

    Google Scholar 

  4. Gilbert, S.F. Developmental Biology, 8th edn, ch. 7, 17 and 19 (Sinauer Associates, Sunderland, Massachusetts, 2006).

    Google Scholar 

  5. Barsoum, I. & Yao, H.H. The road to maleness: from testis to Wolffian duct. Trends Endocrinol. Metab. 17, 223–228 (2006).

    Google Scholar 

  6. Kobayashi, A. & Behringer, R.R. Developmental genetics of the female reproductive tract in mammals. Nat. Rev. Genet. 4, 969–980 (2003).

    Google Scholar 

  7. Seminara, S.B. & Crowley, W.F. Jr. Kisspeptin and GPR54: discovery of a novel pathway in reproduction. J. Neuroendocrinol. 20, 727–731 (2008).

    Google Scholar 

  8. de Roux, N. et al. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc. Natl. Acad. Sci. USA 100, 10972–10976 (2003).

    Google Scholar 

  9. Seminara, S.B. et al. The GPR54 gene as a regulator of puberty. N. Engl. J. Med. 349, 1614–1627 (2003).

    Google Scholar 

  10. Funes, S. et al. The KiSS-1 receptor GPR54 is essential for the development of the murine reproductive system. Biochem. Biophys. Res. Commun. 312, 1357–1363 (2003).

    Google Scholar 

  11. Lapatto, R. et al. Kiss1−/− mice exhibit more variable hypogonadism than Gpr54−/− mice. Endocrinology 148, 4927–4936 (2007).

    Google Scholar 

  12. d'Anglemont de Tassigny, X., et al. Hypogonadotropic hypogonadism in mice lacking a functional Kiss1 gene. Proc. Natl. Acad. Sci. USA 104, 10714–10719 (2007).

    Google Scholar 

  13. Franco, B. et al. A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules. Nature 353, 529–536 (1991).

    Google Scholar 

  14. Legouis, R. et al. The candidate gene for the X-linked Kallmann syndrome encodes a protein related to adhesion molecules. Cell 67, 423–435 (1991).

    Google Scholar 

  15. Layman, L.C. et al. Mutations in gonadotropin-releasing hormone receptor gene cause hypogonadotropic hypogonadism. Nat. Genet. 18, 14–15 (1998).

    Google Scholar 

  16. de Roux, N. et al. A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor. N. Engl. J. Med. 337, 1597–1602 (1997).

    Google Scholar 

  17. Dong, J. et al. Growth differentiation factor-9 is required during early ovarian folliculogenesis. Nature 383, 531–535 (1996).

    Google Scholar 

  18. McNatty, K.P. et al. The oocyte and its role in regulating ovulation rate: a new paradigm in reproductive biology. Reproduction 128, 379–386 (2004).

    Google Scholar 

  19. Palmer, J.S. et al. Novel variants in growth differentiation factor 9 in mothers of dizygotic twins. J. Clin. Endocrinol. Metab. 91, 4713–4716 (2006).

    Google Scholar 

  20. Di Pasquale, E., Beck-Peccoz, P. & Persani, L. Hypergonadotropic ovarian failure associated with an inherited mutation of human bone morphogenetic protein-15 (BMP15) gene. Am. J. Hum. Genet. 75, 106–111 (2004).

    Google Scholar 

  21. Ledig, S., Ropke, A., Haeusler, G., Hinney, B. & Wieacker, P. BMP15 mutations in XX gonadal dysgenesis and premature ovarian failure. Am. J. Obstet. Gynecol. 198, 84.e1–84.e5 (2008).

    Google Scholar 

  22. Sugiura, K. et al. Oocyte-derived BMP15 and FGFs cooperate to promote glycolysis in cumulus cells. Development 134, 2593–2603 (2007).

    Google Scholar 

  23. Hinckley, M., Vaccari, S., Horner, K., Chen, R. & Conti, M. The G-protein–coupled receptors GPR3 and GPR12 are involved in cAMP signaling and maintenance of meiotic arrest in rodent oocytes. Dev. Biol. 287, 249–261 (2005).

    Google Scholar 

  24. Mehlmann, L.M. et al. The Gs-linked receptor GPR3 maintains meiotic arrest in mammalian oocytes. Science 306, 1947–1950 (2004).

    Google Scholar 

  25. Su, Y.Q. et al. Oocyte regulation of metabolic cooperativity between mouse cumulus cells and oocytes: BMP15 and GDF9 control cholesterol biosynthesis in cumulus cells. Development 135, 111–121 (2008).

    Google Scholar 

  26. Kumar, T.R., Wang, Y., Lu, N. & Matzuk, M.M. Follicle stimulating hormone is required for ovarian follicle maturation but not male fertility. Nat. Genet. 15, 201–204 (1997).

    Google Scholar 

  27. Park, J.Y. et al. EGF-like growth factors as mediators of LH action in the ovulatory follicle. Science 303, 682–684 (2004).

    Google Scholar 

  28. Schultz, N., Hamra, F.K. & Garbers, D.L. A multitude of genes expressed solely in meiotic or postmeiotic spermatogenic cells offers a myriad of contraceptive targets. Proc. Natl. Acad. Sci. USA 100, 12201–12206 (2003).

    Google Scholar 

  29. Greenbaum, M.P., Ma, L. & Matzuk, M.M. Conversion of midbodies into germ cell intercellular bridges. Dev. Biol. 305, 389–396 (2007).

    Google Scholar 

  30. Kitada, K. et al. Transposon-tagged mutagenesis in the rat. Nat. Methods 4, 131–133 (2007).

    Google Scholar 

  31. Collier, L.S. & Largaespada, D.A. Transposons for cancer gene discovery: Sleeping Beauty and beyond. Genome Biol. 8 Suppl 1, S15 (2007).

    Google Scholar 

  32. Ro, S. et al. Cloning and expression profiling of testis-expressed piRNA-like RNAs. RNA 13, 1693–1702 (2007).

    Google Scholar 

  33. Du, T. & Zamore, P.D. microPrimer: the biogenesis and function of microRNA. Development 132, 4645–4652 (2005).

    Google Scholar 

  34. Zhang, L. et al. Genomic and epigenetic alterations deregulate microRNA expression in human epithelial ovarian cancer. Proc. Natl. Acad. Sci. USA 105, 7004–7009 (2008).

    Google Scholar 

  35. Nelson, C.P. & Gearhart, J.P. Current views on evaluation, management, and gender assignment of the intersex infant. Nat. Clin. Pract. Urol. 1, 38–43 (2004).

    Google Scholar 

  36. Andersson, M., Page, D.C. & de la Chapelle, A. Chromosome Y–specific DNA is transferred to the short arm of X chromosome in human XX males. Science 233, 786–788 (1986).

    Google Scholar 

  37. Gubbay, J. et al. A gene mapping to the sex-determining region of the mouse Y chromosome is a member of a novel family of embryonically expressed genes. Nature 346, 245–250 (1990).

    Google Scholar 

  38. Foster, J.W. et al. Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. Nature 372, 525–530 (1994).

    Google Scholar 

  39. Wagner, T. et al. Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell 79, 1111–1120 (1994).

    Google Scholar 

  40. Huang, B., Wang, S., Ning, Y., Lamb, A.N. & Bartley, J. Autosomal XX sex reversal caused by duplication of SOX9. Am. J. Med. Genet. 87, 349–353 (1999).

    Google Scholar 

  41. Smyk, M. et al. Male-to-female sex reversal associated with an approximately 250 kb deletion upstream of NR0B1 (DAX1). Hum. Genet. 122, 63–70 (2007).

    Google Scholar 

  42. Zanaria, E. et al. An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature 372, 635–641 (1994).

    Google Scholar 

  43. Bernard, P., Sim, H., Knower, K., Vilain, E. & Harley, V. Human SRY inhibits β-catenin–mediated transcription. Int. J. Biochem. Cell Biol. 40, 2889–2900 (2008).

    Google Scholar 

  44. McElreavey, K., Vilain, E., Abbas, N., Herskowitz, I. & Fellous, M. A regulatory cascade hypothesis for mammalian sex determination: SRY represses a negative regulator of male development. Proc. Natl. Acad. Sci. USA 90, 3368–3372 (1993).

    Google Scholar 

  45. Wilhelm, D., Palmer, S. & Koopman, P. Sex determination and gonadal development in mammals. Physiol. Rev. 87, 1–28 (2007).

    Google Scholar 

  46. Capel, B. R-spondin1 tips the balance in sex determination. Nat. Genet. 38, 1233–1234 (2006).

    Google Scholar 

  47. Parma, P. et al. R-spondin1 is essential in sex determination, skin differentiation and malignancy. Nat. Genet. 38, 1304–1309 (2006).

    Google Scholar 

  48. Jordan, B.K. et al. Up-regulation of WNT-4 signaling and dosage-sensitive sex reversal in humans. Am. J. Hum. Genet. 68, 1102–1109 (2001).

    Google Scholar 

  49. Vainio, S., Heikkila, M., Kispert, A., Chin, N. & McMahon, A.P. Female development in mammals is regulated by Wnt-4 signalling. Nature 397, 405–409 (1999).

    Google Scholar 

  50. Chassot, A.A. et al. Activation of β-catenin signaling by Rspo1 controls differentiation of the mammalian ovary. Hum. Mol. Genet. 17, 1264–1277 (2008).

    Google Scholar 

  51. Maatouk, D.M. et al. Stabilization of β-catenin in XY gonads causes male-to-female sex-reversal. Hum. Mol. Genet. 17, 2949–2955 (2008).

    Google Scholar 

  52. Morris, J.M. The syndrome of testicular feminization in male pseudohermaphrodites. Am. J. Obstet. Gynecol. 65, 1192–1211 (1953).

    Google Scholar 

  53. Behringer, R.R., Eakin, G.S. & Renfree, M.B. Mammalian diversity: gametes, embryos and reproduction. Reprod. Fertil. Dev. 18, 99–107 (2006).

    Google Scholar 

  54. Bogatcheva, N.V. et al. GREAT/LGR8 is the only receptor for insulin-like 3 peptide. Mol. Endocrinol. 17, 2639–2646 (2003).

    Google Scholar 

  55. Nef, S. & Parada, L.F. Cryptorchidism in mice mutant for Insl3. Nat. Genet. 22, 295–299 (1999).

    Google Scholar 

  56. Zimmermann, S. et al. Targeted disruption of the Insl3 gene causes bilateral cryptorchidism. Mol. Endocrinol. 13, 681–691 (1999).

    Google Scholar 

  57. Gorlov, I.P. et al. Mutations of the GREAT gene cause cryptorchidism. Hum. Mol. Genet. 11, 2309–2318 (2002).

    Google Scholar 

  58. Ferlin, A. et al. Paracrine and endocrine roles of insulin-like factor 3. J. Endocrinol. Invest. 29, 657–664 (2006).

    Google Scholar 

  59. Costes, B. et al. Frequent occurrence of the CFTR intron 8 (TG)n 5T allele in men with congenital bilateral absence of the vas deferens. Eur. J. Hum. Genet. 3, 285–293 (1995).

    Google Scholar 

  60. Chillon, M. et al. Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N. Engl. J. Med. 332, 1475–1480 (1995).

    Google Scholar 

  61. Jarvi, K. et al. Cystic fibrosis transmembrane conductance regulator and obstructive azoospermia. Lancet 345, 1578 (1995).

    Google Scholar 

  62. Chu, C.S., Trapnell, B.C., Curristin, S., Cutting, G.R. & Crystal, R.G. Genetic basis of variable exon 9 skipping in cystic fibrosis transmembrane conductance regulator mRNA. Nat. Genet. 3, 151–156 (1993).

    Google Scholar 

  63. Claustres, M. Molecular pathology of the CFTR locus in male infertility. Reprod. Biomed. Online 10, 14–41 (2005).

    Google Scholar 

  64. Disset, A. et al. A T3 allele in the CFTR gene exacerbates exon 9 skipping in vas deferens and epididymal cell lines and is associated with congenital bilateral absence of vas deferens (CBAVD). Hum. Mutat. 25, 72–81 (2005).

    Google Scholar 

  65. Puscheck, E.E. & Cohen, L. Congenital malformations of the uterus: the role of ultrasound. Semin. Reprod. Med. 26, 223–231 (2008).

    Google Scholar 

  66. Robins, J.C. & Carson, S.A. Female fertility: what every urologist must understand. Urol. Clin. North Am. 35, 173–181 (2008).

    Google Scholar 

  67. Van Voorhis, B.J. Ultrasound assessment of the uterus and fallopian tube in infertile women. Semin. Reprod. Med. 26, 232–240 (2008).

    Google Scholar 

  68. Gekas, J. et al. Chromosomal factors of infertility in candidate couples for ICSI: an equal risk of constitutional aberrations in women and men. Hum. Reprod. 16, 82–90 (2001).

    Google Scholar 

  69. Soyal, S.M. et al. Cre-mediated recombination in cell lineages that express the progesterone receptor. Genesis 41, 58–66 (2005).

    Google Scholar 

  70. De Philippo, R.E., Bishop, C.E., Filho, L.F., Yoo, J.J. & Atala, A. Tissue engineering a complete vaginal replacement from a small biopsy of autologous tissue. Transplantation 86, 208–214 (2008).

    Google Scholar 

  71. Montgomery, G.W. et al. The search for genes contributing to endometriosis risk. Hum. Reprod. Update 14, 447–457 (2008).

    Google Scholar 

  72. Matzuk, M.M. Gynecologic diseases get their genes. Nat. Med. 11, 24–26 (2005).

    Google Scholar 

  73. Dinulescu, D.M. et al. Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer. Nat. Med. 11, 63–70 (2005).

    Google Scholar 

  74. Daikoku, T. et al. Conditional loss of uterine Pten unfailingly and rapidly induces endometrial cancer in mice. Cancer Res. 68, 5619–5627 (2008).

    Google Scholar 

  75. Nam Menke, M. & Strauss, J.F. III. Genetics of polycystic ovarian syndrome. Clin. Obstet. Gynecol. 50, 188–204 (2007).

    Google Scholar 

  76. Urbanek, M. The genetics of the polycystic ovary syndrome. Nat. Clin. Pract. Endocrinol. Metab. 3, 103–111 (2007).

    Google Scholar 

  77. Lipshultz, L.I. & Lamb, D.J. Risk of transmission of genetic diseases by assisted reproduction. Nat. Clin. Pract. Urol. 4, 460–461 (2007).

    Google Scholar 

  78. World Health Organization. WHO Laboratory manual for the examination of human semen and sperm-cervical mucus interaction. (Cambridge University Press, Cambridge, 1999).

  79. Krisfalusi, M., Miki, K., Magyar, P.L. & O'Brien, D.A. Multiple glycolytic enzymes are tightly bound to the fibrous sheath of mouse spermatozoa. Biol. Reprod. 75, 270–278 (2006).

    Google Scholar 

  80. Cao, W., Gerton, G.L. & Moss, S.B. Proteomic profiling of accessory structures from the mouse sperm flagellum. Mol. Cell. Proteomics 5, 801–810 (2006).

    Google Scholar 

  81. Martinez-Heredia, J., de Mateo, S., Vidal-Taboada, J.M., Ballesca, J.L. & Oliva, R. Identification of proteomic differences in asthenozoospermic sperm samples. Hum. Reprod. 23, 783–791 (2008).

    Google Scholar 

  82. Eddy, E.M., Toshimori, K. & O'Brien, D.A. Fibrous sheath of mammalian spermatozoa. Microsc. Res. Tech. 61, 103–115 (2003).

    Google Scholar 

  83. Chemes, H.E., Brugo, S., Zanchetti, F., Carrere, C. & Lavieri, J.C. Dysplasia of the fibrous sheath: an ultrastructural defect of human spermatozoa associated with sperm immotility and primary sterility. Fertil. Steril. 48, 664–669 (1987).

    Google Scholar 

  84. Turner, R.M. et al. Molecular genetic analysis of two human sperm fibrous sheath proteins, AKAP4 and AKAP3, in men with dysplasia of the fibrous sheath. J. Androl. 22, 302–315 (2001).

    Google Scholar 

  85. Storm van's Gravesande, K. & Omran, H. Primary ciliary dyskinesia: clinical presentation, diagnosis and genetics. Ann. Med. 37, 439–449 (2005).

    Google Scholar 

  86. Schwabe, G.C. et al. Primary ciliary dyskinesia associated with normal axoneme ultrastructure is caused by DNAH11 mutations. Hum. Mutat. 29, 289–298 (2008).

    Google Scholar 

  87. Zuccarello, D. et al. Mutations in dynein genes in patients affected by isolated non-syndromic asthenozoospermia. Hum. Reprod. 23, 1957–1962 (2008).

    Google Scholar 

  88. Zuccarello, D. et al. A possible association of a human tektin-t gene mutation (A229V) with isolated non-syndromic asthenozoospermia: case report. Hum. Reprod. 23, 996–1001 (2008).

    Google Scholar 

  89. Li, H.G., Ding, X.F., Liao, A.H., Kong, X.B. & Xiong, C.L. Expression of CatSper family transcripts in the mouse testis during post-natal development and human ejaculated spermatozoa: relationship to sperm motility. Mol. Hum. Reprod. 13, 299–306 (2007).

    Google Scholar 

  90. Jin, J. et al. Catsper3 and catsper4 are essential for sperm hyperactivated motility and male fertility in the mouse. Biol. Reprod. 77, 37–44 (2007).

    Google Scholar 

  91. Carlson, A.E. et al. CatSper1 required for evoked Ca2+ entry and control of flagellar function in sperm. Proc. Natl. Acad. Sci. USA 100, 14864–14868 (2003).

    Google Scholar 

  92. Quill, T.A., Ren, D., Clapham, D.E. & Garbers, D.L. A voltage-gated ion channel expressed specifically in spermatozoa. Proc. Natl. Acad. Sci. USA 98, 12527–12531 (2001).

    Google Scholar 

  93. Navarro, B., Kirichok, Y. & Clapham, D.E. KSper, a pH-sensitive K+ current that controls sperm membrane potential. Proc. Natl. Acad. Sci. USA 104, 7688–7692 (2007).

    Google Scholar 

  94. Ren, D. et al. A sperm ion channel required for sperm motility and male fertility. Nature 413, 603–609 (2001).

    Google Scholar 

  95. Qi, H. et al. All four CatSper ion channel proteins are required for male fertility and sperm cell hyperactivated motility. Proc. Natl. Acad. Sci. USA 104, 1219–1223 (2007).

    Google Scholar 

  96. Nikpoor, P., Mowla, S.J., Movahedin, M., Ziaee, S.A. & Tiraihi, T. CatSper gene expression in postnatal development of mouse testis and in subfertile men with deficient sperm motility. Hum. Reprod. 19, 124–128 (2004).

    Google Scholar 

  97. Wang, D. et al. A sperm-specific Na+/H+ exchanger (sNHE) is critical for expression and in vivo bicarbonate regulation of the soluble adenylyl cyclase (sAC). Proc. Natl. Acad. Sci. USA 104, 9325–9330 (2007).

    Google Scholar 

  98. Quill, T.A., Wang, D. & Garbers, D.L. Insights into sperm cell motility signaling through sNHE and the CatSpers. Mol. Cell. Endocrinol. 250, 84–92 (2006).

    Google Scholar 

  99. Kruger, T.F. et al. Predictive value of abnormal sperm morphology in in vitro fertilization. Fertil. Steril. 49, 112–117 (1988).

    Google Scholar 

  100. Kruger, T.F. et al. New method of evaluating sperm morphology with predictive value for human in vitro fertilization. Urology 30, 248–251 (1987).

    Google Scholar 

  101. Dieterich, K. et al. Homozygous mutation of AURKC yields large-headed polyploid spermatozoa and causes male infertility. Nat. Genet. 39, 661–665 (2007).

    Google Scholar 

  102. Dam, A.H. et al. Homozygous mutation in SPATA16 is associated with male infertility in human globozoospermia. Am. J. Hum. Genet. 81, 813–820 (2007).

    Google Scholar 

  103. Coburn, M., Kim, E.D. & Wheeler, T.M. Testicular biopsy in male infertility evaluation. ch. 12, 219–248 (Mosby Year Book, St. Louis, Missouri, 1997).

    Google Scholar 

  104. Oates, R.D. Clinical and diagnostic features of patients with suspected Klinefelter syndrome. J. Androl. 24, 49–50 (2003).

    Google Scholar 

  105. Cheung, S.W. et al. Microarray-based CGH detects chromosomal mosaicism not revealed by conventional cytogenetics. Am. J. Med. Genet. A. 143A, 1679–1686 (2007).

    Google Scholar 

  106. Cheung, S.W. et al. Development and validation of a CGH microarray for clinical cytogenetic diagnosis. Genet. Med. 7, 422–432 (2005).

    Google Scholar 

  107. Reijo, R. et al. Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene. Nat. Genet. 10, 383–393 (1995).

    Google Scholar 

  108. Kuroda-Kawaguchi, T. et al. The AZFc region of the Y chromosome features massive palindromes and uniform recurrent deletions in infertile men. Nat. Genet. 29, 279–286 (2001).

    Google Scholar 

  109. Repping, S. et al. Recombination between palindromes P5 and P1 on the human Y chromosome causes massive deletions and spermatogenic failure. Am. J. Hum. Genet. 71, 906–922 (2002).

    Google Scholar 

  110. Repping, S. 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. 35, 247–251 (2003).

    Google Scholar 

  111. Hopps, C.V. et al. Detection of sperm in men with Y chromosome microdeletions of the AZFa, AZFb and AZFc regions. Hum. Reprod. 18, 1660–1665 (2003).

    Google Scholar 

  112. Hassold, T. & Hunt, P. To err (meiotically) is human: the genesis of human aneuploidy. Nat. Rev. Genet. 2, 280–291 (2001).

    Google Scholar 

  113. Gonsalves, J. et al. Defective recombination in infertile men. Hum. Mol. Genet. 13, 2875–2883 (2004).

    Google Scholar 

  114. Sun, F. et al. Reduced meiotic recombination on the XY bivalent is correlated with an increased incidence of sex chromosome aneuploidy in men with non-obstructive azoospermia. Mol. Hum. Reprod. 14, 399–404 (2008).

    Google Scholar 

  115. Sun, F. et al. The relationship between meiotic recombination in human spermatocytes and aneuploidy in sperm. Hum. Reprod. 23, 1691–1697 (2008).

    Google Scholar 

  116. Hassold, T., Hall, H. & Hunt, P. The origin of human aneuploidy: where we have been, where we are going. Hum. Mol. Genet. 16, R203–R208 (2007).

    Google Scholar 

  117. Lamb, N.E., Sherman, S.L. & Hassold, T.J. Effect of meiotic recombination on the production of aneuploid gametes in humans. Cytogenet. Genome Res. 111, 250–255 (2005).

    Google Scholar 

  118. Moosani, N. et al. Chromosomal analysis of sperm from men with idiopathic infertility using sperm karyotyping and fluorescence in situ hybridization. Fertil. Steril. 64, 811–817 (1995).

    Google Scholar 

  119. Egozcue, J. et al. Meiotic abnormalities in infertile males. Cytogenet. Genome Res. 111, 337–342 (2005).

    Google Scholar 

  120. Carrell, D.T. The clinical implementation of sperm chromosome aneuploidy testing: pitfalls and promises. J. Androl. 29, 124–133 (2008).

    Google Scholar 

  121. Cherry, S.M. et al. The Mre11 complex influences DNA repair, synapsis, and crossing over in murine meiosis. Curr. Biol. 17, 373–378 (2007).

    Google Scholar 

  122. Kuznetsov, S. et al. RAD51C deficiency in mice results in early prophase I arrest in males and sister chromatid separation at metaphase II in females. J. Cell Biol. 176, 581–592 (2007).

    Google Scholar 

  123. Bannister, L.A. et al. A dominant, recombination-defective allele of Dmc1 causing male-specific sterility. PLoS Biol. 5, e105 (2007).

    Google Scholar 

  124. Wolstenholme, J. & Angell, R.R. Maternal age and trisomy–a unifying mechanism of formation. Chromosoma 109, 435–438 (2000).

    Google Scholar 

  125. Pellestor, F., Andreo, B., Arnal, F., Humeau, C. & Demaille, J. Maternal aging and chromosomal abnormalities: new data drawn from in vitro unfertilized human oocytes. Hum. Genet. 112, 195–203 (2003).

    Google Scholar 

  126. Hodges, C.A., Revenkova, E., Jessberger, R., Hassold, T.J. & Hunt, P.A. SMC1β-deficient female mice provide evidence that cohesins are a missing link in age-related nondisjunction. Nat. Genet. 37, 1351–1355 (2005).

    Google Scholar 

  127. Vogt, E., Kirsch-Volders, M., Parry, J. & Eichenlaub-Ritter, U. Spindle formation, chromosome segregation and the spindle checkpoint in mammalian oocytes and susceptibility to meiotic error. Mutat. Res. 651, 14–29 (2008).

    Google Scholar 

  128. Steptoe, P.C. & Edwards, R.G. Birth after the reimplantation of a human embryo. Lancet 312, 366 (1978).

    Google Scholar 

  129. Palermo, G., Joris, H., Devroey, P. & Van Steirteghem, A.C. Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet 340, 17–18 (1992).

    Google Scholar 

  130. Devroey, P. et al. Normal fertilization of human oocytes after testicular sperm extraction and intracytoplasmic sperm injection. Fertil. Steril. 62, 639–641 (1994).

    Google Scholar 

  131. Silber, S.J. et al. Conventional in vitro fertilization versus intracytoplasmic sperm injection for patients requiring microsurgical sperm aspiration. Hum. Reprod. 9, 1705–1709 (1994).

    Google Scholar 

  132. Andersen, A.N. et al. Assisted reproductive technology in Europe, 2003. Results generated from European registers by ESHRE. Hum. Reprod. 22, 1513–1525 (2007).

    Google Scholar 

  133. Harari, O., Bourne, H., Baker, G., Gronow, M. & Johnston, I. High fertilization rate with intracytoplasmic sperm injection in mosaic Klinefelter's syndrome. Fertil. Steril. 63, 182–184 (1995).

    Google Scholar 

  134. Tournaye, H. et al. Testicular sperm recovery in nine 47,XXY Klinefelter patients. Hum. Reprod. 11, 1644–1649 (1996).

    Google Scholar 

  135. Kent-First, M.G. et al. The incidence and possible relevance of Y-linked microdeletions in babies born after intracytoplasmic sperm injection and their infertile fathers. Mol. Hum. Reprod. 2, 943–950 (1996).

    Google Scholar 

  136. Testart, J. et al. Intracytoplasmic sperm injection in infertile patients with structural chromosome abnormalities. Hum. Reprod. 11, 2609–2612 (1996).

    Google Scholar 

  137. Pettigrew, R. et al. A pregnancy following PGD for X-linked dominant [correction of X-linked autosomal dominant] incontinentia pigmenti (Bloch-Sulzberger syndrome): case report. Hum. Reprod. 15, 2650–2652 (2000).

    Google Scholar 

  138. Liu, J. et al. Successful fertilization and establishment of pregnancies after intracytoplasmic sperm injection in patients with globozoospermia. Hum. Reprod. 10, 626–629 (1995).

    Google Scholar 

  139. Verpoest, W. et al. Real and expected delivery rates of patients with myotonic dystrophy undergoing intracytoplasmic sperm injection and preimplantation genetic diagnosis. Hum. Reprod. 23, 1654–1660 (2008).

    Google Scholar 

  140. Sermon, K. et al. PGD in the lab for triplet repeat diseases - myotonic dystrophy, Huntington's disease and Fragile-X syndrome. Mol. Cell. Endocrinol. 183 Suppl 1, S77–S85 (2001).

    Google Scholar 

  141. Iacobelli, M. et al. Birth of a healthy female after preimplantation genetic diagnosis for Charcot-Marie-Tooth type X. Reprod. Biomed. Online 7, 558–562 (2003).

    Google Scholar 

  142. De Vos, A. et al. Pregnancy after preimplantation genetic diagnosis for Charcot-Marie-Tooth disease type 1A. Mol. Hum. Reprod. 4, 978–984 (1998).

    Google Scholar 

  143. Lofgren, A. et al. Preimplantation diagnosis for Charcot-Marie-Tooth type 1A. Ann. NY Acad. Sci. 883, 460–462 (1999).

    Google Scholar 

  144. D'Hauwers, K.W., Feitz, W.F. & Kremer, J.A. Bladder exstrophy and male fertility: pregnancies after ICSI with ejaculated or epididymal sperm. Fertil. Steril. 89, 387–389 (2008).

    Google Scholar 

  145. Lai, R. et al. Twin pregnancy achieved through TESE in an adult male exstrophy. J. Assist. Reprod. Genet. 19, 245–247 (2002).

    Google Scholar 

  146. Verpoest, W., Platteau, P., Van Steirteghem, A. & Devroey, P. Pregnancy in a couple with a male partner born with severe bladder exstrophy. Reprod. Biomed. Online 8, 240–242 (2004).

    Google Scholar 

  147. Liu, J. et al. Birth after preimplantation diagnosis of the cystic fibrosis Δ F508 mutation by polymerase chain reaction in human embryos resulting from intracytoplasmic sperm injection with epididymal sperm. J. Am. Med. Assoc. 272, 1858–1860 (1994).

    Google Scholar 

  148. Manno, M., Tomei, F., Maruzzi, D., Di Filippo, L. & Garbeglio, A. A case report of CUAVD with azoospermia: a proposal of a rational diagnostic approach. Arch. Ital. Urol. Androl. 75, 25–27 (2003).

    Google Scholar 

  149. Papadimas, J. et al. Therapeutic approach of immotile cilia syndrome by intracytoplasmic sperm injection: a case report. Fertil. Steril. 67, 562–565 (1997).

    Google Scholar 

  150. Cayan, S. Conaghan, J., Schriockm E.D., Ryan, I.P., Black, L.D. & Turek, P.J. Birth after intracytoplasmic sperm injection with use of testicular sperm from men with Kartagener/immotile cilia syndrome. Fertil. Steril. 76, 612–614 (2001).

    Google Scholar 

  151. Nijs, M. et al. Fertilizing ability of immotile spermatozoa after intracytoplasmic sperm injection. Hum. Reprod. 11, 2180–2185 (1996).

    Google Scholar 

  152. von Zumbusch, A. et al. Birth of healthy children after intracytoplasmic sperm injection in two couples with male Kartagener's syndrome. Fertil. Steril. 70, 643–646 (1998).

    Google Scholar 

  153. Mahmoud, A.M., Comhaire, F.H., Abdel-Rahim, D.E. & Abdel-Hafez, K.M. Conception rates and assisted reproduction in subfertility due to unilateral cryptorchidism. Andrologia 28, 141–144 (1996).

    Google Scholar 

  154. Ao, A., Wells, D., Handyside, A.H., Winston, R.M. & Delhanty, J.D. Preimplantation genetic diagnosis of inherited cancer: familial adenomatous polyposis coli. J. Assist. Reprod. Genet. 15, 140–144 (1998).

    Google Scholar 

  155. Alukal, J.P. & Lamb, D.J. Intracytoplasmic sperm injection (ICSI)—what are the risks? Urol. Clin. North. Am. 35, 277–288 (2008).

    Google Scholar 

  156. Kent-First, M.G., Kol, S., Muallem, A., Blazer, S. & Itskovitz-Eldor, J. Infertility in intracytoplasmic-sperm-injection–derived sons. Lancet 348, 332 (1996).

    Google Scholar 

  157. Veld, P.A. et al. Two cases of Robertsonian translocations in oligozoospermic males and their consequences for pregnancies induced by intracytoplasmic sperm injection. Hum. Reprod. 12, 1642–1644 (1997).

    Google Scholar 

  158. Meschede, D. Louwen, F., Eiben, B. & Horst, J. Intracytoplasmic sperm injection pregnancy with fetal trisomy 9p resulting from a balanced paternal translocation. Hum. Reprod. 12, 1913–1914 (1997).

    Google Scholar 

  159. Trimborn, M. et al. Prenatal diagnosis and molecular cytogenetic characterization of an unusual complex structural rearrangement in a pregnancy following intracytoplasmic sperm injection (ICSI). J. Histochem. Cytochem. 53, 351–354 (2005).

    Google Scholar 

  160. Jean, M. et al. Prenatal diagnosis of ring chromosome 14 after intracytoplasmic sperm injection. Fertil. Steril. 67, 164–165 (1997).

    Google Scholar 

  161. Schuffner, A., Centa, L., Reggiani, C. & Costa, S. Acral and renal malformations following ICSI. Arch. Androl. 52, 145–148 (2006).

    Google Scholar 

  162. Dalmia, R., Young, P. Sunada, G.V. A case of triploidy. Fertil. Steril. 83, 462–463 (2005).

    Google Scholar 

  163. Naylor, C.S. T.K., Asrat T Trisomy 13 in one fetus from a twin gestation after intracytoplasmic sperm injection. A case report. J. Reprod. Med. 46, 497–498 (2001).

    Google Scholar 

  164. Carrell, D.T. Wilcox, A.L., Udoff, L.C., Thorp, C. & Campbell, B. Chromosome 15 aneuploidy in the sperm and conceptus of a sibling with variable familial expression of round-headed sperm syndrome. Fertil. Steril. 76, 1258–1260 (2001).

    Google Scholar 

  165. Bartels, I. Schlosser, M., Bartz, U.G. & Pauer, H.U. Paternal origin of trisomy 21 following intracytoplasmic sperm injection (ICSI). Humanit. Rep. 13, 3345–3346 (1998).

    Google Scholar 

  166. Van Opstal, D. et al. Determination of the parent of origin in nine cases of prenatally detected chromosome aberrations found after intracytoplasmic sperm injection. Hum. Reprod. 12, 682–686 (1997).

    Google Scholar 

  167. Belva, F. et al. Medical outcome of 8-year-old singleton ICSI children (born >or=32 weeks' gestation) and a spontaneously conceived comparison group. Hum. Reprod. 22, 506–515 (2007).

    Google Scholar 

  168. Delhanty, J.D., Handyside, A.H., Winston, R.M. & Hughes, M. Sex determination of preimplantation embryos. Lancet 343, 549 (1994).

    Google Scholar 

  169. Handyside, A.H., Lesko, J.G., Tarin, J.J., Winston, R.M. & Hughes, M.R. Birth of a normal girl after in vitro fertilization and preimplantation diagnostic testing for cystic fibrosis. N. Engl. J. Med. 327, 905–909 (1992).

    Google Scholar 

  170. Verlinsky, Y., Rechitsky, S., Schoolcraft, W., Strom, C. & Kuliev, A. Preimplantation diagnosis for Fanconi anemia combined with HLA matching. J. Am. Med. Assoc. 285, 3130–3133 (2001).

    Google Scholar 

  171. Practice Committee of the Society for Assisted Reproductive Technology & Practice Committee of the American Society for Reproductive Medicine. Guidelines on number of embryos transferred. Fertil. Steril. 86, S51–S52 (2006).

  172. Sakkas, D. & Gardner, D.K. Noninvasive methods to assess embryo quality. Curr. Opin. Obstet. Gynecol. 17, 283–288 (2005).

    Google Scholar 

  173. Katz-Jaffe, M.G., Schoolcraft, W.B. & Gardner, D.K. Analysis of protein expression (secretome) by human and mouse preimplantation embryos. Fertil. Steril. 86, 678–685 (2006).

    Google Scholar 

  174. Papanikolaou, E.G. et al. Live birth rates after transfer of equal number of blastocysts or cleavage-stage embryos in IVF. A systematic review and meta-analysis. Hum. Reprod. 23, 91–99 (2008).

    Google Scholar 

  175. McArthur, S.J., Leigh, D., Marshall, J.T., de Boer, K.A. & Jansen, R.P. Pregnancies and live births after trophectoderm biopsy and preimplantation genetic testing of human blastocysts. Fertil. Steril. 84, 1628–1636 (2005).

    Google Scholar 

  176. National Institutes of Health. National Institutes of Health Guidelines for Research Using Human Pluripotent Stem Cells. Fed. Regist. 65, 51891 (1999).

  177. Aitken, R.J. et al. As the world grows: contraception in the 21st century. J. Clin. Invest. 118, 1330–1343 (2008).

    Google Scholar 

  178. Spehr, M. et al. Identification of a testicular odorant receptor mediating human sperm chemotaxis. Science 299, 2054–2058 (2003).

    Google Scholar 

  179. Tash, J.S. et al. A novel potent indazole carboxylic acid derivative blocks spermatogenesis and is contraceptive in rats after a single oral dose. Biol. Reprod. 78, 1127–1138 (2008).

    Google Scholar 

  180. Mruk, D.D., Silvestrini, B. & Cheng, C.Y. Anchoring junctions as drug targets: role in contraceptive development. Pharmacol. Rev. 60, 146–180 (2008).

    Google Scholar 

  181. Geremia, R., Boitani, C., Conti, M. & Monesi, V. RNA synthesis in spermatocytes and spermatids and preservation of meiotic RNA during spermiogenesis in the mouse. Cell Differ. 5, 343–355 (1977).

    Google Scholar 

  182. Monesi, V. Synthetic activities during spermatogenesis in the mouse RNA and protein. Exp. Cell Res. 39, 197–224 (1965).

    Google Scholar 

  183. Kumar, G., Patel, D. & Naz, R.K. c-MYC mRNA is present in human sperm cells. Cell. Mol. Biol. Res. 39, 111–117 (1993).

    Google Scholar 

  184. Kramer, J.A. & Krawetz, S.A. RNA in spermatozoa: implications for the alternative haploid genome. Mol. Hum. Reprod. 3, 473–478 (1997).

    Google Scholar 

  185. Krawetz, S.A. On the significance of RNA in human sperm. Zhonghua Nan Ke Xue 11, 170–174 (2005).

    Google Scholar 

  186. Ostermeier, G.C., Dix, D.J., Miller, D., Khatri, P. & Krawetz, S.A. Spermatozoal RNA profiles of normal fertile men. Lancet 360, 772–777 (2002).

    Google Scholar 

  187. Ostermeier, G.C., Miller, D., Huntriss, J.D., Diamond, M.P. & Krawetz, S.A. Reproductive biology: delivering spermatozoan RNA to the oocyte. Nature 429, 154 (2004).

    Google Scholar 

  188. Yatsenko, A.N. et al. Non-invasive genetic diagnosis of male infertility using spermatozoal RNA: KLHL10 mutations in oligozoospermic patients impair homodimerization. Hum. Mol. Genet. 15, 3411–3419 (2006).

    Google Scholar 

  189. Platts, A.E. et al. Success and failure in human spermatogenesis as revealed by teratozoospermic RNAs. Hum. Mol. Genet. 16, 763–773 (2007).

    Google Scholar 

  190. Meistrich, M.L. et al. Recovery of sperm production after chemotherapy for osteosarcoma. Cancer 63, 2115–2123 (1989).

    Google Scholar 

  191. Meistrich, M.L., Wilson, G., Brown, B.W., da Cunha, M.F. & Lipshultz, L.I. Impact of cyclophosphamide on long-term reduction in sperm count in men treated with combination chemotherapy for Ewing and soft tissue sarcomas. Cancer 70, 2703–2712 (1992).

    Google Scholar 

  192. Pryzant, R.M., Meistrich, M.L., Wilson, G., Brown, B. & McLaughlin, P. Long-term reduction in sperm count after chemotherapy with and without radiation therapy for non-Hodgkin's lymphomas. J. Clin. Oncol. 11, 239–247 (1993).

    Google Scholar 

  193. Brinster, R.L. & Zimmerman, J.W. Spermatogenesis following male germ-cell transplantation. Proc. Natl. Acad. Sci. USA 91, 11298–11302 (1994).

    Google Scholar 

  194. Geens, M. et al. Autologous spermatogonial stem cell transplantation in man: current obstacles for a future clinical application. Hum. Reprod. Update 14, 121–130 (2008).

    Google Scholar 

  195. Hou, M., Andersson, M., Eksborg, S., Soder, O. & Jahnukainen, K. Xenotransplantation of testicular tissue into nude mice can be used for detecting leukemic cell contamination. Hum. Reprod. 22, 1899–1906 (2007).

    Google Scholar 

  196. Jahnukainen, K., Hou, M., Petersen, C., Setchell, B. & Soder, O. Intratesticular transplantation of testicular cells from leukemic rats causes transmission of leukemia. Cancer Res. 61, 706–710 (2001).

    Google Scholar 

  197. Guan, K. et al. Pluripotency of spermatogonial stem cells from adult mouse testis. Nature 440, 1199–1203 (2006).

    Google Scholar 

  198. Kanatsu-Shinohara, M. et al. Pluripotency of a single spermatogonial stem cell in mice. Biol. Reprod. 78, 681–687 (2008).

    Google Scholar 

  199. Takehashi, M. et al. Production of knockout mice by gene targeting in multipotent germline stem cells. Dev. Biol. 312, 344–352 (2007).

    Google Scholar 

  200. Conrad, S. et al. Generation of pluripotent stem cells from adult human testis. Nature published online, doi:10.1038/nature07404 (8 October 2008).

  201. Nayernia, K. et al. Derivation of male germ cells from bone marrow stem cells. Lab. Invest. 86, 654–663 (2006).

    Google Scholar 

  202. Nayernia, K. et al. In vitro–differentiated embryonic stem cells give rise to male gametes that can generate offspring mice. Dev. Cell 11, 125–132 (2006).

    Google Scholar 

  203. Brinster, R.L. Male germline stem cells: from mice to men. Science 316, 404–405 (2007).

    Google Scholar 

  204. Oatley, J.M. & Brinster, R.L. Regulation of spermatogonial stem cell self-renewal in mammals. Annu. Rev. Cell Dev. Biol. 24, 263–285 (2008).

    Google Scholar 

  205. Kanatsu-Shinohara, M. et al. Production of knockout mice by random or targeted mutagenesis in spermatogonial stem cells. Proc. Natl. Acad. Sci. USA 103, 8018–8023 (2006).

    Google Scholar 

  206. Chen, C. et al. ERM is required for transcriptional control of the spermatogonial stem cell niche. Nature 436, 1030–1034 (2005).

    Google Scholar 

  207. Hamra, F.K., Chapman, K.M., Nguyen, D. & Garbers, D.L. Identification of neuregulin as a factor required for formation of aligned spermatogonia. J. Biol. Chem. 282, 721–730 (2007).

    Google Scholar 

  208. Nagano, M. et al. Transgenic mice produced by retroviral transduction of male germ-line stem cells. Proc. Natl. Acad. Sci. USA 98, 13090–13095 (2001).

    Google Scholar 

  209. Ryu, B.Y. et al. Efficient generation of transgenic rats through the male germline using lentiviral transduction and transplantation of spermatogonial stem cells. J. Androl. 28, 353–360 (2007).

    Google Scholar 

  210. Kanatsu-Shinohara, M., Toyokuni, S. & Shinohara, T. Transgenic mice produced by retroviral transduction of male germ line stem cells in vivo. Biol. Reprod. 71, 1202–1207 (2004).

    Google Scholar 

  211. Hermann, B.P. et al. Characterization, cryopreservation, and ablation of spermatogonial stem cells in adult rhesus macaques. Stem Cells 25, 2330–2338 (2007).

    Google Scholar 

  212. Barritt, J.A., Brenner, C.A., Malter, H.E. & Cohen, J. Mitochondria in human offspring derived from ooplasmic transplantation. Hum. Reprod. 16, 513–516 (2001).

    Google Scholar 

  213. Brenner, C.A., Barritt, J.A., Willadsen, S. & Cohen, J. Mitochondrial DNA heteroplasmy after human ooplasmic transplantation. Fertil. Steril. 74, 573–578 (2000).

    Google Scholar 

  214. Eggan, K., Jurga, S., Gosden, R., Min, I.M. & Wagers, A.J. Ovulated oocytes in adult mice derive from non-circulating germ cells. Nature 441, 1109–1114 (2006).

    Google Scholar 

  215. Johnson, J., Canning, J., Kaneko, T., Pru, J.K. & Tilly, J.L. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature 428, 145–150 (2004).

    Google Scholar 

  216. Johnson, J. et al. Oocyte generation in adult mammalian ovaries by putative germ cells in bone marrow and peripheral blood. Cell 122, 303–315 (2005).

    Google Scholar 

  217. Kerr, J.B. et al. Quantification of healthy follicles in the neonatal and adult mouse ovary: evidence for maintenance of primordial follicle supply. Reproduction 132, 95–109 (2006).

    Google Scholar 

  218. Begum, S., Papaioannou, V.E. & Gosden, R.G. The oocyte population is not renewed in transplanted or irradiated adult ovaries. Hum. Reprod. 23, 2326–2330 (2008).

    Google Scholar 

  219. Bristol-Gould, S.K. et al. Fate of the initial follicle pool: empirical and mathematical evidence supporting its sufficiency for adult fertility. Dev. Biol. 298, 149–154 (2006).

    Google Scholar 

  220. Sekido, R., Bar, I., Narvaez, V., Penny, G. & Lovell-Badge, R. SOX9 is up-regulated by the transient expression of SRY specifically in Sertoli cell precursors. Dev. Biol. 274, 271–279 (2004).

    Google Scholar 

  221. DiNapoli, L., Batchvarov, J. & Capel, B. FGF9 promotes survival of germ cells in the fetal testis. Development 133, 1519–1527 (2006).

    Google Scholar 

  222. Binnerts, M.E. et al. R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6. Proc. Natl. Acad. Sci. USA 104, 14700–14705 (2007).

    Google Scholar 

  223. Yao, H.H., Aardema, J. & Holthusen, K. Sexually dimorphic regulation of inhibin β B in establishing gonadal vasculature in mice. Biol. Reprod. 74, 978–983 (2006).

    Google Scholar 

  224. Bernstein, E. et al. Dicer is essential for mouse development. Nat. Genet. 35, 215–217 (2003).

    Google Scholar 

  225. Chong, M.M., Rasmussen, J.P., Rundensky, A.Y. & Littman, D.R. The RNAseIII enzyme Drosha is critical in T cells for preventing lethal inflammatory disease. J. Exp. Med. 205, 2005–2017 (2008).

    Google Scholar 

  226. Otsuka, M. et al. Impaired microRNA processing causes corpus luteum insufficiency and infertility in mice. J. Clin. Invest. 118, 1944–1954 (2008).

    Google Scholar 

  227. Murchison, E.P. et al. Critical roles for Dicer in the female germline. Genes Dev. 21, 682–693 (2007).

    Google Scholar 

  228. Watanabe, T. et al. Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes. Nature 453, 539–543 (2008).

    Google Scholar 

  229. Tam, O.H. et al. Pseudogene-derived small interfering RNAs regulate gene expression in mouse oocytes. Nature 453, 534–538 (2008).

    Google Scholar 

  230. Tang, F. et al. Maternal microRNAs are essential for mouse zygotic development. Genes Dev. 21, 644–648 (2007).

    Google Scholar 

  231. Hayashi, K. et al. MicroRNA biogenesis is required for mouse primordial germ cell development and spermatogenesis. PLoS ONE 3, e1738 (2008).

    Google Scholar 

  232. Maatouk, D.M., Loveland, K.L., McManus, M.T., Moore, K. & Harfe, B.D. Dicer1 is required for differentiation of the mouse male germline. Biol. Reprod. 79, 696–703 (2008).

    Google Scholar 

  233. Nagaraja, A.K. et al. Deletion of Dicer in somatic cells of the female reproductive tract causes sterility. Mol. Endocrinol. 22, 2336–2352 (2008).

    Google Scholar 

  234. Hong, X., Luense, L.J., McGinnis, L.K., Nothnick, W.B. & Christenson, L.K. Dicer1 is essential for female fertility and normal development of the female reproductive system. Endocrinology published online, doi:10.1210/en.2008-0294 (14 August 2008).

    Google Scholar 

  235. Kuramochi-Miyagawa, S. et al. Mili, a mammalian member of piwi family gene, is essential for spermatogenesis. Development 131, 839–849 (2004).

    Google Scholar 

  236. Kuramochi-Miyagawa, S. et al. DNA methylation of retrotransposon genes is regulated by Piwi family members MILI and MIWI2 in murine fetal testes. Genes Dev. 22, 908–917 (2008).

    Google Scholar 

  237. Carmell, M.A. et al. MIWI2 is essential for spermatogenesis and repression of transposons in the mouse male germline. Dev. Cell 12, 503–514 (2007).

    Google Scholar 

  238. Deng, W. & Lin, H. miwi, a murine homolog of piwi, encodes a cytoplasmic protein essential for spermatogenesis. Dev. Cell 2, 819–830 (2002).

    Google Scholar 

Download references

Acknowledgements

Reproductive biology and cancer research in the Matzuk and Lamb laboratories have been supported by US National Institutes of Health grants P01 HD36289, R01 DK078121, R01 HD32067, R01 HD42500, R01 CA60651, R37 HD33438, U54 HD07495, T32 DK00763 and K12 DK083014, by the US Department of Defense, US Army Materiel Command PC061154 and by the Ovarian Cancer Research Fund. We thank our many colleagues, S. Alexander, S. Han, M. Hsieh, R. Khavari, M. Louet, S. Mukhajee, A. Nagaraja, R. Nalam, S. Whirledge, and H. Yao, for their outstanding insights and critiques of this review. We apologize to colleagues whose work is not referenced herein because of space limitations. The supplementary information online contains more detailed references.

Author information

Authors and Affiliations

Authors

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Matzuk, M., Lamb, D. The biology of infertility: research advances and clinical challenges. Nat Med 14, 1197–1213 (2008). https://doi.org/10.1038/nm.f.1895

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.f.1895

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing