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Lower sperm DNA fragmentation after r-FSH administration in functional hypogonadotropic hypogonadism

Journal of Assisted Reproduction and Genetics volume 30, pages 497–503 (2013)Cite this article

Abstract

Purpose

An observational clinical and molecular study was designed to evaluate the effects of the administration of recombinant human FSH on sperm DNA fragmentation in men with a non-classical form of hypogonadotropic hypogonadism and idiopathic oligoasthenoteratozoospermia.

Methods

In the study were included 53 men with a non-classical form of hypogonadotropic hypogonadism and idiopathic oligoasthenoteratozoospermia. In all patients, sperm DNA fragmentation index (DFI), assessed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) in situ DNA nick end-labelling (TUNEL) assay, was evaluated before starting the treatment with 150 IU of recombinant human FSH, given three times a week for at least 3 months. Patients’ semen analysis and DNA fragmentation index were re-evaluated after the 3-month treatment period.

Results

After recombinant human FSH therapy, we did not find any differences in terms of sperm count, motility and morphology. The average DNA fragmentation index was significantly reduced (21.15 vs 15.2, p < 0.05), but we found a significant reduction in patients with high basal DFI values (>15 %), while no significant variation occurred in the patients with DFI values ≤15 %.

Conclusions

Recombinant human FSH administration improves sperm DNA integrity in hypogonadotropic hypogonadism and idiopathic oligoasthenoteratozoospermia men with DNA fragmentation index value >15 % .

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References

  1. Adler ID. Spermatogenesis and mutagenicity of environmental hazards: extrapolation of genetic risk from mouse to man. Andrologia. 2000;32:233–7.

    PubMed  CAS  Article  Google Scholar 

  2. Aitken RJ, De Iuliis GN. On the possible origins of DNA damage in human spermatozoa. Mol Hum Reprod. 2010;16:3–13.

    PubMed  CAS  Article  Google Scholar 

  3. Arnaldi G, Balercia G, Barbatelli G, Mantero F. Effects of long-term treatment with human pure follicle-stimulating hormone on semen parameters and sperm-cell ultrastructure in idiopathic oligoteratoasthenozoospermia. Andrologia. 2000;32:155–61.

    PubMed  CAS  Article  Google Scholar 

  4. Attia AM, Al-Inany HG, Farquhar C, Proctor M: Gonadotrophins for idiopathic male factor subfertility. Cochrane Database Syst Rev 2007, CD005071.

  5. Ben-Rafael Z, Farhi J, Feldberg D, Bartoov B, Kovo M, Eltes F, et al. Follicle-stimulating hormone treatment for men with idiopathic oligoteratoasthenozoospermia before in vitro fertilization: the impact on sperm microstructure and fertilization potential. Fertil Steril. 2000;73:24–30.

    PubMed  CAS  Article  Google Scholar 

  6. Berkovitz A, Eltes F, Ellenbogen A, Peer S, Feldberg D, Bartoov B. Does the presence of nuclear vacuoles in human sperm selected for ICSI affect pregnancy outcome? Hum Reprod. 2006;21:1787–90.

    PubMed  Article  Google Scholar 

  7. Bungum M, Humaidan P, Axmon A, Spano M, Bungum L, Erenpreiss J, et al. Sperm DNA integrity assessment in prediction of assisted reproduction technology outcome. Hum Reprod. 2007;22:174–9.

    PubMed  CAS  Article  Google Scholar 

  8. Calogero A, Polosa R, Perdichizzi A, Guarino F, La Vignera S, Scarfia A, et al. Cigarette smoke extract immobilizes human spermatozoa and induces sperm apoptosis. Reprod Biomed Online. 2009;19:564–71.

    PubMed  Article  Google Scholar 

  9. Caroppo E, Niederberger C, Vizziello GM, D’Amato G. Recombinant human follicle-stimulating hormone as a pretreatment for idiopathic oligoasthenoteratozoospermic patients undergoing intracytoplasmic sperm injection. Fertil Steril. 2003;80:1398–403.

    PubMed  Article  Google Scholar 

  10. Chemes EH, Rawe YV. Sperm pathology: a step beyond descriptive morphology. Origin, characterization and fertility potential of abnormal sperm phenotypes in infertile men. Hum Reprod Updat. 2003;9:405–28.

    Article  Google Scholar 

  11. Colacurci N, Monti MG, Fornaro F, Izzo G, Izzo P, Trotta C, et al. Recombinant Human FSH Reduces Sperm DNA Fragmentation in Men with Idiopathic Oligoasthenoteratozoospermia. J Androl. 2012;33:588–93.

    PubMed  CAS  Article  Google Scholar 

  12. Comhaire FH, Christophe AB, Zalata AA, Dhooge WS, Mahmoud AM, Depuydt CE. The effects of combined conventional treatment, oral antioxidants and essential fatty acids on sperm biology in subfertile men. Prostaglandins Leukot Essent Fatty Acids. 2000;63:159–65.

    PubMed  CAS  Article  Google Scholar 

  13. Efesoy O, Çayan S, Akbay E. The efficacy of recombinant human follicle-stimulating hormone in the treatment of various types of male-factor infertility at a single University Hospital. J Androl. 2009;30(6):679–84.

    PubMed  CAS  Article  Google Scholar 

  14. Evenson DP, Jost LK, Marshall D, Zinaman MJ, Clegg E, Purvis K, et al. Utility of the sperm chromatin structure assay as a diagnostic and prognostic tool in the human fertility clinic. Hum Reprod. 1999;14:1039–49.

    PubMed  CAS  Article  Google Scholar 

  15. Foresta C, Bettella A, Garolla A, Ambrosini G, Ferlin A. Treatment of male idiopathic infertility with recombinant human follicle-stimulating hormone: a prospective, controlled, randomized clinical study. Fertil Steril. 2005;84:654–61.

    PubMed  CAS  Article  Google Scholar 

  16. Foresta C, Selice R, Garolla A, Ferlin A. Follicle-stimulating hormone treatment of male infertility. Curr Opin Urol. 2008;18:602–7.

    PubMed  Article  Google Scholar 

  17. Frydman N, Prisant N, Hesters L, Frydman R, Tachdjian G, Cohen-Bacrie P, et al. Adequate ovarian follicular status does not prevent the decrease in pregnancy rates associated with high sperm DNA fragmentation. Fertil Steril. 2008;89:92–7.

    PubMed  CAS  Article  Google Scholar 

  18. Gandini L, Lombardo F, Paoli D, Caponecchia L, Familiari G, Verlengia C, et al. Study of apoptotic DNA fragmentation in human spermatozoa. Hum Reprod. 2000;15:830–9.

    PubMed  CAS  Article  Google Scholar 

  19. Greco E, Romano S, Iacobelli M, Ferrero S, Baroni E, Minasi MG, et al. ICSI in cases of sperm DNA damage: beneficial effect of oral antioxidant treatment. Hum Reprod. 2005;20:2590–4.

    PubMed  CAS  Article  Google Scholar 

  20. Grunewald S, Paasch U, Glander HJ. Enrichment of non-apoptotic human spermatozoa after cryopreservation by immunomagnetic cell sorting. Cell Tissue Bank. 2001;2:127–33.

    PubMed  CAS  Article  Google Scholar 

  21. Guzick DS, Overstreet JW, Factor-Litvak P, Brazil CK, Nakajima ST, Coutifaris C, et al. Sperm morphology, motility, and concentration in fertile and infertile men. N Engl J Med. 2001;345:1388–93.

    PubMed  CAS  Article  Google Scholar 

  22. Hikim AP, Wang C, Leung A, Swerdloff RS. Involvement of apoptosis in the induction of germ cell degeneration in adult rats after gonadotropin-releasing hormone antagonist treatment. Endocrinology. 1995;136:2770–5.

    PubMed  CAS  Article  Google Scholar 

  23. Jakab A, Sakkas D, Delpiano E, Cayli S, Kovanci E, Ward D, et al. Intracytoplasmic sperm injection: a novel selection method for sperm with normal frequency of chromosomal aneuploidies. Fertil Steril. 2005;84:1665–73.

    PubMed  Article  Google Scholar 

  24. Jones R, Mann T, Sherins R. Peroxidative breakdown of phospholipids in human spermatozoa, spermicidal properties of fatty acid peroxides, and protective action of seminal plasma. Fertil Steril. 1979;31:531–7.

    PubMed  CAS  Google Scholar 

  25. Jones R, Mann T, Sherins RJ. Adverse effects of peroxidized lipid on human spermatozoa. Proc R Soc Lond B Biol Sci. 1978;201:413–7.

    PubMed  CAS  Article  Google Scholar 

  26. Ku WW, Wine RN, Chae BY, Ghanayem BI, Chapin RE. Spermatocyte toxicity of 2-methoxyethanol (ME) in rats and guinea pigs: evidence for the induction of apoptosis. Toxicol Appl Pharmacol. 1995;134:100–10.

    PubMed  CAS  Article  Google Scholar 

  27. Leduc F, Nkoma GB, Boissonneault G. Spermiogenesis and DNA repair: a possible etiology of human infertility and genetic disorders. Syst Biol Reprod Med. 2008;54:3–10.

    PubMed  CAS  Article  Google Scholar 

  28. Lenzi A, Balercia G, Bellastella A, Colao A, Fabbri A, Foresta C, et al. Epidemiology, diagnosis, and treatment of male hypogonadotropic hypogonadism. J Endocrinol Invest. 2009;32:934–8.

    PubMed  CAS  Google Scholar 

  29. Lewis SE. Is sperm evaluation useful in predicting human fertility? Reproduction. 2007;134:31–40.

    PubMed  CAS  Article  Google Scholar 

  30. Lewis SE, Aitken RJ. DNA damage to spermatozoa has impacts on fertilization and pregnancy. Cell Tissue Res. 2005;322:33–41.

    PubMed  CAS  Article  Google Scholar 

  31. Li LH, Wine RN, Chapin RE. 2-Methoxyacetic acid (MAA)-induced spermatocyte apoptosis in human and rat testes: an in vitro comparison. J Androl. 1996;17:538–49.

    PubMed  CAS  Google Scholar 

  32. Lin MH, Kuo-Kuang Lee R, Li SH, Lu CH, Sun FJ, Hwu YM. Sperm chromatin structure assay parameters are not related to fertilization rates, embryo quality, and pregnancy rates in in vitro fertilization and intracytoplasmic sperm injection, but might be related to spontaneous abortion rates. Fertil Steril. 2008;90:352–9.

    PubMed  Article  Google Scholar 

  33. Lopes S, Sun JG, Jurisicova A, Meriano J, Casper RF. Sperm deoxyribonucleic acid fragmentation is increased in poor-quality semen samples and correlates with failed fertilization in intracytoplasmic sperm injection. Fertil Steril. 1998;69:528–32.

    PubMed  CAS  Article  Google Scholar 

  34. Lue TF. Topical and oral agents for erectile dysfunction. J Formos Med Assoc. 1999;98:233–41.

    PubMed  CAS  Google Scholar 

  35. Marcon L, Boissonneault G. Transient DNA strand breaks during mouse and human spermiogenesis new insights in stage specificity and link to chromatin remodeling. Biol Reprod. 2004;70:910–8.

    PubMed  CAS  Article  Google Scholar 

  36. Matsumoto AM, Snyder PJ, Bhasin S, Martin K, Weber T, Winters S, et al. Stimulation of spermatogenesis with recombinant human follicle-stimulating hormone (follitropin alfa; GONAL-f®): long-term treatment in azoospermic men with hypogonadotropic hypogonadism. Fertil Steril. 2009;92:979–90.

    PubMed  CAS  Article  Google Scholar 

  37. Meistrich ML. Effects of chemotherapy and radiotherapy on spermatogenesis. Eur Urol. 1993;23:136–41. discussion 42.

    PubMed  CAS  Google Scholar 

  38. Menezo YJ, Hazout A, Panteix G, Robert F, Rollet J, Cohen-Bacrie P, et al. Antioxidants to reduce sperm DNA fragmentation: an unexpected adverse effect. Reprod Biomed Online. 2007;14:418–21.

    PubMed  CAS  Article  Google Scholar 

  39. Morris ID, Ilott S, Dixon L, Brison DR. The spectrum of DNA damage in human sperm assessed by single cell gel electrophoresis (Comet assay) and its relationship to fertilization and embryo development. Hum Reprod. 2002;17:990–8.

    PubMed  CAS  Article  Google Scholar 

  40. Moustafa MH, Sharma RK, Thornton J, Mascha E, Abdel-Hafez MA, Thomas Jr AJ, et al. Relationship between ROS production, apoptosis and DNA denaturation in spermatozoa from patients examined for infertility. Hum Reprod. 2004;19:129–38.

    PubMed  CAS  Article  Google Scholar 

  41. Obasaju M, Kadam A, Sultan K, Fateh M, Munne S. Sperm quality may adversely affect the chromosome constitution of embryos that result from intracytoplasmic sperm injection. Fertil Steril. 1999;72:1113–5.

    PubMed  CAS  Article  Google Scholar 

  42. Ozmen B, Caglar GS, Koster F, Schopper B, Diedrich K, Al-Hasani S. Relationship between sperm DNA damage, induced acrosome reaction and viability in ICSI patients. Reprod Biomed Online. 2007;15:208–14.

    PubMed  CAS  Article  Google Scholar 

  43. Phillip M, Arbelle JE, Segev Y, Parvari R. Male hypogonadism due to a mutation in the gene for the beta-subunit of follicle-stimulating hormone. N Engl J Med. 1998;338:1729–32.

    PubMed  CAS  Article  Google Scholar 

  44. Practice Committee of American Society for Reproductive Medicine. The clinical utility of sperm DNA integrity testing. Fertil Steril. 2008;90(5 Suppl):S178–80.

    Google Scholar 

  45. Ruwanpura SM, McLachlan RI, Stanton PG, Loveland KL, Meachem SJ. Pathways involved in testicular germ cell apoptosis in immature rats after FSH suppression. J Endocrinol. 2008;197:35–43.

    PubMed  CAS  Article  Google Scholar 

  46. Safarinejad MR, Shafiei N, Safarinejad S. Association of polymorphisms in the estrogen receptors alpha, and beta (ESR1, ESR2) with the occurrence of male infertility and semen parameters. J Steroid Biochem Mol Biol. 2010;122:193–203.

    PubMed  CAS  Article  Google Scholar 

  47. Safarinejad MR, Shafiei N, Safarinejad S. Evaluating the role of the FSH receptor gene Thr307-Ala and Asn680-Ser polymorphisms in male infertility and their association with semen quality and reproductive hormones. BJU Int. 2011;108:E117–25.

    PubMed  Article  Google Scholar 

  48. Sakkas D, Urner F, Bianchi PG, Bizzaro D, Wagner I, Jaquenoud N, et al. Sperm chromatin anomalies can influence decondensation after intracytoplasmic sperm injection. Hum Reprod. 1996;11:837–43.

    PubMed  CAS  Article  Google Scholar 

  49. Sakkas D, Alvarez JG. Sperm DNA fragmentation: mechanisms of origin, impact on reproductive outcome, and analysis. Fertil Steril. 2010;93:1027–36.

    PubMed  CAS  Article  Google Scholar 

  50. Sakkas D, Mariethoz E, Manicardi G, Bizzaro D, Bianchi PG, Bianchi U. Origin of DNA damage in ejaculated human spermatozoa. Rev Reprod. 1999;4:31–7.

    PubMed  CAS  Article  Google Scholar 

  51. Sakkas D, Seli E, Bizzaro D, Tarozzi N, Manicardi GC. Abnormal spermatozoa in the ejaculate: abortive apoptosis and faulty nuclear remodelling during spermatogenesis. Reprod Biomed Online. 2003;7:428–32.

    PubMed  Article  Google Scholar 

  52. Sawyer DE, Roman SD, Aitken RJ. Relative susceptibilities of mitochondrial and nuclear DNA to damage induced by hydrogen peroxide in two mouse germ cell lines. Redox Rep. 2001;6:182–4.

    PubMed  CAS  Article  Google Scholar 

  53. Selice R, Garolla A, Pengo M, Caretta N, Ferlin A, Foresta C. The response to FSH treatment in oligozoospermic men depends on FSH receptor gene polymorphisms. Int J Androl. 2011;34:306–12.

    PubMed  CAS  Article  Google Scholar 

  54. Seminara SB, Crowley Jr WF. Perspective: the importance of genetic defects in humans in elucidating the complexities of the hypothalamic-pituitary-gonadal axis. Endocrinology. 2001;142:2173–7.

    PubMed  CAS  Article  Google Scholar 

  55. Sinha Hikim AP, Rajavashisth TB, Sinha Hikim I, Lue Y, Bonavera JJ, Leung A, et al. Significance of apoptosis in the temporal and stage-specific loss of germ cells in the adult rat after gonadotropin deprivation. Biol Reprod. 1997;57:1193–201.

    PubMed  CAS  Article  Google Scholar 

  56. Sinisi AA, Esposito D, Bellastella G, Maione L, Palumbo V, Gandini L, et al. Efficacy of recombinant human follicle stimulating hormone at low doses in inducing spermatogenesis and fertility in hypogonadotropic hypogonadism. J Endocrinol Invest. 2010;33:618–23.

    PubMed  CAS  Google Scholar 

  57. Spano M, Bonde JP, Hjollund HI, Kolstad HA, Cordelli E, Leter G. Sperm chromatin damage impairs human fertility. The Danish First Pregnancy Planner Study Team. Fertil Steril. 2000;73:43–50.

    PubMed  CAS  Article  Google Scholar 

  58. Strehler E, Sterzik K, De Santo M, Abt M, Wiedemann R, Bellati U, et al. The effect of follicle-stimulating hormone therapy on sperm quality: an ultrastructural mathematical evaluation. J Androl. 1997;18:439–47.

    PubMed  CAS  Google Scholar 

  59. Tapanainen JS, Aittomaki K, Min J, Vaskivuo T, Huhtaniemi IT. Men homozygous for an inactivating mutation of the follicle-stimulating hormone (FSH) receptor gene present variable suppression of spermatogenesis and fertility. Nat Genet. 1997;15:205–6.

    PubMed  CAS  Article  Google Scholar 

  60. Tarozzi N, Bizzaro D, Flamigni C, Borini A. Clinical relevance of sperm DNA damage in assisted reproduction. Reprod Biomed Online. 2007;14:746–57.

    PubMed  CAS  Article  Google Scholar 

  61. Tesarik J, Guido M, Mendoza C, Greco E. Human spermatogenesis in vitro: respective effects of follicle-stimulating hormone and testosterone on meiosis, spermiogenesis, and Sertoli cell apoptosis. J Clin Endocrinol Metab. 1998;83:4467–73.

    PubMed  CAS  Article  Google Scholar 

  62. Tesarik J, Martinez F, Rienzi L, Iacobelli M, Ubaldi F, Mendoza C, et al. In-vitro effects of FSH and testosterone withdrawal on caspase activation and DNA fragmentation in different cell types of human seminiferous epithelium. Hum Reprod. 2002;17:1811–9.

    PubMed  CAS  Article  Google Scholar 

  63. Walczak-Jedrzejowska R, Slowikowska-Hilczer J, Marchlewsk K, Oszukowska E, Kula K. During seminiferous tubule maturation testosterone and synergistic action of FSH with estradiol support germ cell survival while estradiol alone has pro-apoptotic effect. Folia Histochem Cytobiol. 2007;45 Suppl 1:S59–64.

    PubMed  Google Scholar 

  64. Warne DW, Decosterd G, Okada H, Yano Y, Koide N, Howles CM. A combined analysis of data to identify predictive factors for spermatogenesis in men with hypogonadotropic hypogonadism treated with recombinant human follicle-stimulating hormone and human chorionic gonadotropin. Fertil Steril. 2009;92:594–604.

    PubMed  CAS  Article  Google Scholar 

  65. World Health Organization. WHO laboratory manual for the examination of human semen and sperm-cervical mucus interaction. Cambridge: Cambridge Academic Press; 2010.

    Google Scholar 

  66. Zhang Y, Wang H, Wang L, Zhou Z, Sha J, Mao Y, et al. The clinical significance of sperm DNA damage detection combined with routine semen testing in assisted reproduction. Mol Med Rep. 2008;1:617–24.

    PubMed  CAS  Google Scholar 

  67. Zini A, Boman JM, Belzile E, Ciampi A. Sperm DNA damage is associated with an increased risk of pregnancy loss after IVF and ICSI: systematic review and meta-analysis. Hum Reprod. 2008;23:2663–8.

    PubMed  CAS  Article  Google Scholar 

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Acknowledgements

This work was supported by grants from MIUR (ex 60 %).

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Authors and Affiliations

  1. Centro di Biologia della Riproduzione, via V. Villareale 54, 90141, Palermo, Italy

    Giovanni Ruvolo, Anna Maria Brucculeri & Ettore Cittadini

  2. Dipartimento di Scienze e Tecnologie Molecolari e Biomolecolari, University of Palermo, viale delle Scienze, Edificio 16, 90128, Palermo, Italy

    Maria Carmela Roccheri & Liana Bosco

  3. Merck-Serono, Via Casilina, 112, Rome, Italy

    Salvatore Longobardi

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  1. Giovanni Ruvolo
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  2. Maria Carmela Roccheri
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  5. Ettore Cittadini
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  6. Liana Bosco
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Correspondence to Giovanni Ruvolo.

Additional information

Capsule Recombinant human FSH administration improves sperm DNA integrity but not sperm count, motility and morphology, in men with a non‐classical form of hypogonadotropic hypo‐gonadism and idiopathic oligoasthenoteratozoospermia with baseline DNA fragmentation index value >15 %.

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Ruvolo, G., Roccheri, M.C., Brucculeri, A.M. et al. Lower sperm DNA fragmentation after r-FSH administration in functional hypogonadotropic hypogonadism. J Assist Reprod Genet 30, 497–503 (2013). https://doi.org/10.1007/s10815-013-9951-y

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Keywords

  • Apoptosis
  • Gametogenesis
  • DNA
  • Sperm