Skip to main content

Advertisement

SpringerLink
Log in

Increased apoptosis of germ cells in patients with AZFc deletions

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

Abstract

Purpose

AZFc deletions are associated with variable testicular histology ranging from the Sertoli cell only to spermatogenic arrest and hypospermatogenesis. Such variable phenotypes may be explained by progressive germ cell regression over time. Increased apoptosis is likely responsible for progressive regression of spermatogenic potential. This study evaluated germ cell apoptosis as a cause of the progressive decrease in the number of germ cells in patients with AZFc deletions.

Methods

This study evaluated germ cell apoptosis in patients with AZFc deletions. A total of 151 patients who were diagnosed with either severe oligozoospermia or non-obstructive azoospermia were screened for Y chromosome microdeletions. Germ cell apoptosis was examined using terminal deoxy-nucleotidyl transferase-mediated digoxigenin-dUTP nick-end labeling (TUNEL) on formalin-fixed 5-µm sections of testicular specimens.

Results

Seven out of 117 (6.0%) patients with azoospermia and 4 of 34 (11.8%) patients with severe oligozoospermia had Y chromosome microdeletions. The percentage of apoptotic germ cells in the testes of patients with AZFc deletions were significantly increased compared to those of patients without AZFc deletions.

Conclusions

These results suggest that increased apoptosis of germ cells is responsible for the progressive decline of spermatogenic potential in patients with AZFc deletions.

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

Similar content being viewed by others

References

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

    Article  CAS  PubMed  Google Scholar 

  2. Huang WJ, Lin Y, Hsiao KN, Eilber KS, Salido EC. Restricted expression of the human DAZ protein in premeiotic germ cells. Hum Reprod. 2008;23:1280–9.

    Article  CAS  PubMed  Google Scholar 

  3. Girardi SK, Mielnik A, Schlegel PN. Submicrocsopic deletions in the Y chromosome of infertile men. Hum Reprod. 1997;12:1635–41.

    Article  CAS  PubMed  Google Scholar 

  4. Simoni M, Carani C, Gromoll J, Meschede D, Dworniczak B, et al. Screening for deletions of the Y chromosome involving the DAZ gene in azoospermia and severe oligozoospermia. Fertil Steril. 1997;67:542–7.

    Article  CAS  PubMed  Google Scholar 

  5. Calogero AE, Garofalo MR, Barone N, Palma AD, Vicari E, et al. Spontaneous regression over time of the germinal epithelium in a Y chromosome-microdeleted patient. Hum Reprod. 2001;16:1845–8.

    Article  CAS  PubMed  Google Scholar 

  6. Dada R, Gupa NP, Kucheria K. Molecular screening for Yq microdeletion in men with idiopathic oligozoospermia and azoospermia. J Biosci. 2003;28:163–8.

    Article  CAS  PubMed  Google Scholar 

  7. Dada R, Gupta NP, Kucheria K. Yq microdeletions—Azoospermia factor candidate genes and spermatogenic arrest. J Biomol Tech. 2004;15:176–83.

    PubMed  Google Scholar 

  8. Ferilin A, Arredi B, Speltra E, Cazzadore C, Selice R, et al. Molecular and clinical characterization of Y chromosome microdeletions in infertile men. A 10-year experience in Italy. J Clin Endocrinol Metab. 2007;92:762–70.

    Article  Google Scholar 

  9. Tesarik J, Greco E, Cohen-Bacrie P, Mendoza C. Germ cell apoptosis in men with complete and incomplete spermiogenesis failure. Mol, Hum Reprod. 1998;4:757–62.

    Article  CAS  Google Scholar 

  10. Lin WW, Lipshultz LI, Lamb DJ, Kim ED, Wheeler TM. In situ end-labeling of human testicular tissue demonstrates increased apoptosis in conditions of abnormal spermatogenesis. Fertil Steril. 1997;68:1065–9.

    Article  CAS  PubMed  Google Scholar 

  11. Takagi S, Itoh N, Kimura M, Sasao T, Tsukamoto T. Spermatogonial proliferation and apoptosis in hypospermatogenesis associated with nonobstructive azoospermia. Fertil Steril. 2001;76:901–7.

    Article  CAS  PubMed  Google Scholar 

  12. Kim S, Yoon Y, Park Y, Seo JT, Kim JH. Involvement of the Fas-Fas ligand system and active caspase-3 in abnormal apoptosis in human testis with maturation arrest and Seltoli cell-only syndrome. Fertil Steril. 2007;87:547–53.

    Article  CAS  PubMed  Google Scholar 

  13. McLachlan RI, Meyts ER, Hoei-Hansen CE, Kretser DM, Skakkebaek NS. Histological evaluation of the human testis—approaches to optimizing the clinical value of the assessment. Hum Reprod. 2007;22:2–16.

    Article  CAS  PubMed  Google Scholar 

  14. Sawai H, Komori S, Koyama K. Molecular analysis of the Y chromosome AZFc region in Japanese infertile males with spermatogenic defects. J Reprod Immunol. 2002;53:37–44.

    Article  CAS  PubMed  Google Scholar 

  15. Carvalho CMB, Fujisawa M, Shirakawa T, Gotoh A, Kamidono S, et al. Lack of association between Y chromosome haplogroups and male infertility in Japanese men. Am J Med Genet A. 2003;116:152–8.

    Article  Google Scholar 

  16. Nagata Y, Fujita K, Banzai J, Kojima Y, Kashima K, et al. Seminal plasma inhibin B level is a useful predictor of the success of conventional testicular sperm extraction in patients with non-obstructive azoospermia. J Obstet Gynaecol Res. 2005;31:384–8.

    Article  CAS  PubMed  Google Scholar 

  17. Oates RD, Silber S, Brown LG, Page DC. Clinical characterization of 42 oligospermic or azoospermic men with microdeletion of the AZFc region of the Y chromosome, and of 18 children conceived via ICSI. Hum Reprod. 2002;17:2813–24.

    Article  CAS  PubMed  Google Scholar 

  18. Frydelund-Larsen L, Krausz C, Leffers H, Andersson AM, Carlsen E, et al. Inhibin B: A marker for the functional state of the seminiferous epithelium in patients with asoospermia factor c microdeletions. J Clin Endocrinol Metab. 2002;87:5618–24.

    Article  CAS  PubMed  Google Scholar 

  19. Dunkel L, Hirvonen V, Erkkila K. Clinical aspects of male germ cell apoptosis during testis development and spermatogenesis. Cell Death Differ. 1997;4:171–9.

    Article  CAS  PubMed  Google Scholar 

  20. Rajpurkar A, Jiang Y, Dhabuwala CB, Dunbar JC, Li H. Cigarette smoking induces apoptosis in rat testis. J Environ Pathol Toxicol Oncol. 2002;21:243–8.

    CAS  PubMed  Google Scholar 

  21. Cozzolino DJ, Lipshultz LI. Varicocele as a progressive lesion: positive effect of varicocele repair. Hum Reprod Update. 2001;7:55–8.

    Article  CAS  PubMed  Google Scholar 

  22. Hassan A, EL-Nashar EM, Mostafa T. Programmed cell death in varicocele-bearing testes. Androlagia. 2009;41:39–45.

    Article  CAS  Google Scholar 

  23. Skaletsky H, Kuroda-Kawaguchi T, Minx PJ, Cordum HS, Hillier L, et al. The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature. 2003;423:825–37.

    Article  CAS  PubMed  Google Scholar 

  24. Maines JZ, Wasserman SA. Post-transcriptional regulation of the meiotic Cdc25 protein Twine by the Dazl orthologue Boule. Nat Cell Biol. 1999;1:171–4.

    Article  CAS  PubMed  Google Scholar 

  25. Venables JP, Ruggiu M, Cooke HJ. The RNA-binding specificity of the mouse Dazl protein. Nucleic Acids Res. 2001;29:2479–83.

    Article  CAS  PubMed  Google Scholar 

  26. Morgan DO. Prnciples of CDK regulation. Nature. 1995;374:131–4.

    Article  CAS  PubMed  Google Scholar 

  27. Wickramasinghe D, Becker S, Ernst MK, Resnick JL, Centanni JM, et al. Two CDC25 homologues are differentially expressed during mouse development. Development. 1995;121:2047–56.

    CAS  PubMed  Google Scholar 

  28. Mizoguchi S, Kim KH. Expression of cdc25 phosphatases in germ cells of the rat testis. Biol Reprod. 1997;56:1474–81.

    Article  CAS  PubMed  Google Scholar 

  29. Kar S, Wang M, Carr BI. 2-methoxyestradiol inhibits hepatocellular carcinoma cell growth by inhibiting Cdc25 and inducing cell cycle arrest and apoptosis. Cancer Chemother Pharmacol. 2008;62:831–40.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We appreciate the excellent technical assistance of Miss Ai Ikarasi and Mrs. Hiroimi Ihana.

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-Dori, Niigata, 951-8520, Japan

    Kyoko Yamada, Kazuyuki Fujita, Jinhua Quan, Masayuki Sekine, Katsunori Kashima, Tetsuro Yahata & Kenichi Tanaka

Authors
  1. Kyoko Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kazuyuki Fujita
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jinhua Quan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masayuki Sekine
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Katsunori Kashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tetsuro Yahata
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kenichi Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kazuyuki Fujita.

Additional information

Capsule Males carrying AZFc deletions exhibit diminished sperm cell numbers due to an enhanced incidence of apoptosis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yamada, K., Fujita, K., Quan, J. et al. Increased apoptosis of germ cells in patients with AZFc deletions. J Assist Reprod Genet 27, 293–297 (2010). https://doi.org/10.1007/s10815-010-9400-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10815-010-9400-0

Keywords

Search

Navigation