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Complete Sperm Suppression in Rats With Dienogest Plus Testosterone Undecanoate Is Facilitated Through Apoptosis in Testicular Cells

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Abstract

Complete suppression of the production of sperm in rats with dienogest (DNG, 40 mg/kg body weight [bw]) plus testosterone undecanoate (TU, 25 mg/kg bw), every 45 days, was found to be associated with a significant increase in germ cell apoptosis. Caspase 3 activity and expression in testis were simultaneously upregulated. Rise in the activities of caspase 8 and 9 was associated with overexpression of upstream marker proteins from extrinsic (Fas [Fatty acid synthase], FasL [Fatty acid synthase ligand], and caspase 8) and intrinsic (Bax [Bcl2-associated-x protein], Bcl2 [B-cell lymphoma 2], and caspase 9) pathways of apoptosis. Apart from the germ cells, interstitial cell apoptosis was also observed along with a decline in the number of functional Leydig cells. It is therefore concluded that complete suppression of the production of sperm with DNG + TU is facilitated mainly through the removal of precursor germ cells through apoptosis. The process is largely modulated by upregulation of upstream and downstream marker proteins from intrinsic as well as extrinsic pathway of metazoan apoptosis.

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References

  1. Li J-W, Gu Y-Q. Predictors for partial suppression of spermatogenesis of hormonal male contraception. Asian J Androl. 2008; 10:723–730.

    Article  CAS  PubMed  Google Scholar 

  2. Ly LP, Liu PY, Handelsman DJ. Rates of suppression and recovery of human sperm output in testosterone-based hormonal contraceptive regimens. Hum Reprod. 2005;20:1733–1740.

    Article  CAS  PubMed  Google Scholar 

  3. Anderson RA, Wallace AM, Kicman AT, Wu FCW. Comparison between testosterone enanthate induced azoospermia and oligospermia in the male contraceptive study. IV. Suppression of endogenous testicular and adrenal androgens. Hum Reprod. 1997;12(8):1657–1662.

    Article  CAS  PubMed  Google Scholar 

  4. Misro MM, Chaki SP, Kaushik M, Nadan D. Trials for development of a once-a-month injectable male contraceptive using dienogest plus testosterone Contraception. 2009;79(6):488–497.

    Article  CAS  PubMed  Google Scholar 

  5. World Health Organization. Task force on methods for the regulation of male fertility. Rates of testosterone induced suppression to severe oligozoospermia or azoospermia in two multinational clinical studies. Int J Androl. 1995;18(3):157–165.

    Article  Google Scholar 

  6. Matsumoto AM. Is high doses testosterone an effective male contraceptive agent? Fertil Steril. 1988;50(2):324–328.

  7. Meena R, Misro MM, Ghosh D, Nandan D. Extended intervention time and evaluation of sperm suppression by dienogest plus testosteerone undecanoate in male rat. Contraception. 2012; 85(1):113–121.

    Article  CAS  PubMed  Google Scholar 

  8. Meena R, Misro MM, Ghosh D, Nandan D. Complete sperm suppression induced by dienogest plus testosterone undecanoate is associated with downregulation in the expression of upstream steroidogenic enzyme genes in rat testis. Contraception. 2012; 86(2):163–171.

    Article  CAS  PubMed  Google Scholar 

  9. Maheshwari A, Misro MM, Aggarwal A, Sharma RK. N-acetyl-L-cysteine modulates multiple signaling pathways to rescue male germ cells from apoptosis induced by chronic hCG administration to rats. Apoptosis. 2012;17(6):551–565.

    Article  CAS  PubMed  Google Scholar 

  10. Wu FC. Hormonal approaches to male contraception: approaching reality. Mol cell Endocrinol. 2006;250(1–2):2–7.

    Article  CAS  PubMed  Google Scholar 

  11. Anderson RA. Hormonal contraception in the male. Br Med Bull. 2000;56(3):717–728.

    Article  CAS  PubMed  Google Scholar 

  12. Manetti GJ, Honig SC. Update on male hormonal contraception: is the vasectomy in jeoparady? Int J Impot Res. 2010;22(3): 159–170.

    Article  CAS  PubMed  Google Scholar 

  13. World Health Organization. Task force on methods for the regulation of male fertility. Contraceptive efficacy of testosterone induced azoospermia and oligospermia in normal men. Fertil Steril. 1996;5:821–829.

    Article  Google Scholar 

  14. Meriggiola MC, Bremner WJ. Androgen combination regimens for male contraception. J Androl. 1997;18(3):240–244.

    CAS  PubMed  Google Scholar 

  15. Bebb RA, Anawalt BD, Christensen RB, Paulsen CA, Bremner WJ, Matsumoto AM. Combined administration of levonorgestrel and testosterone induces more rapid and effective suppression of spermatogenesis than testosterone alone: a promising male contraceptive approach. J Clin Endocrinol. 1996;81(2):757–762.

    CAS  Google Scholar 

  16. Handelsman DJ, Conway AJ, Howe CJ, Turner L, Mackey MA. Establishing the minimum effective dose and additive effects of depot progestin in suppression of human spermatogenesis by a testosterone depot. J Clin Endocrinol Metab. 1996;81(11): 4113–4121.

    CAS  PubMed  Google Scholar 

  17. Meriggiola MC, Bremner WJ, Paulsen CA, et al A combined regimen of cyproterone acetate and testosterone enanthate as a potentially highly effective male contraceptive. J Clin Endocrinol Metab. 1996;81(8):3018–3023.

    CAS  PubMed  Google Scholar 

  18. Meriggiola MC, Bremner WJ, Costantino A, Di Cintio G, Flamigni C. Low dose of crypreterone acetate and testosterone enanthate for contraception in men. Hum Reprod. 1998;13(5): 1225–1229.

    Article  CAS  PubMed  Google Scholar 

  19. Anawalt BD, Bebb RA, Bremner WJ, Matsumoto AM. A lower dosage levonorgestrel and testosterone combination effectively suppresses spermatogenesis and circulating gonadotropin levels with fewer metabolic effects than higher dosage combinations. J Androl. 1999;20(3):407–414.

    CAS  PubMed  Google Scholar 

  20. Anawalt BD, Herbst KL, Matsumoto AM, Mulders TM, Coelingh-Bennink HJ, Bremner WJ. Desogestrel plus testosterone effectively suppresses spermatogenesis but also causes modest weight gain and high-density lipoprotein suppression. Fertil Steril. 2000;74(4):707–714.

    Article  CAS  PubMed  Google Scholar 

  21. Kamischke A, Venherm S, Ploger D, von Eckardstein S, Nieschlag E. Intramuscular testosterone undecanoate and norethisterone enanthate in a clinical trial for male contraception. J Clin Endocrinol Metab. 2001;86(1):303–309.

    CAS  PubMed  Google Scholar 

  22. Kinninburg D, Anderson RA, Baired DT. Suppression of spermatogenesis with desogestrel and testosterone pellets is not enhanced by addition of finsteride. J Androl. 2001;22:88–95.

    Google Scholar 

  23. Zirkin BR, Santulli R, Awoniyi CA, Ewing LL. Maintenance of advance spermatogenic cells in the adult rat testis: quantitative relationship to testosterone concentration within the testis. Endocrinology. 1989;124:3043–3049.

    Article  CAS  PubMed  Google Scholar 

  24. Page ST, Kalhorn TF, Bremner WJ, Anawalt BD, Matusumoto AM, Amory JK. Intratesticular androgens and spermatogenesis during severe gonadotropin suppression induced by male hormonal contraceptive treatment. J Androl. 2007;28:734–741.

    Article  CAS  PubMed  Google Scholar 

  25. Meriggiola MC, Farley TMM, Mbizvo MT. A review of androgen-progestin regimens for male contraception. J Androl. 2003;24(4):466–483.

    Article  CAS  PubMed  Google Scholar 

  26. Aggarwal A, Misro MM, Maheshwari A, Sehgal N, Nandan D. Adverse effects associated with persistent stimulation of Leydig cells with hCG in vitro. Mol Reprod Dev. 2009;76(11):1076–1083.

    Article  CAS  PubMed  Google Scholar 

  27. Aggarwal A, Misro MM, Maheshwari A, Sehgal N. Differential modulation of apoptotic gene expression by NAC in Leydig cells stimulated persistently with hCG in vitro. Mol Cell Endocrinol. 2012;348(1):155–164.

    Article  PubMed  Google Scholar 

  28. Koji T. Male germ cell death in mouse testes: possible involvement of Fas and Fas ligand. Med Electron Microsc. 2001;34(4):213–222.

    Article  CAS  PubMed  Google Scholar 

  29. Giampietri C, Petrungaro S, Coluccia P, et al. Germ cell apoptosis control during spermatogenesis. Contraception. 2005;72:298–302.

    Article  CAS  PubMed  Google Scholar 

  30. Bartke A. Apoptosis of male germ cells, a generalized or a cell type-specific phenomenon? Endocrinology. 1995;136(1):3–4.

    Article  CAS  PubMed  Google Scholar 

  31. Billig H, Furuta I, Rivier C, Tapanainen J, Parvinen M, Hsueh AJ. Apoptosis in testis germ cells: developmental changes in gonadotropin dependence and localization to selective tubule stages. Endocrinology. 1995;136(1):5–12.

    Article  CAS  PubMed  Google Scholar 

  32. Lue Y, Wang C, Cui Y, et al. Levonorgestrel enhances spermatogenesis suppression by testosterone with greater alteration in testicular gene expression in men. Biol Reprod. 2009;80:484–492.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Pentikainen V, Erkkila K, Dunkel L. Fas regulates germ cell apoptosis in the human testis in vitro. Am J Physiol. 1999;276(2 pt 1):E310–E316.

    CAS  PubMed  Google Scholar 

  34. Tripathi R, Mishra DP, Shaha C. Male germ cell development: turning on the apoptotic pathways. J Reprod Immunol. 2009; 83(1):31–35.

    Article  CAS  PubMed  Google Scholar 

  35. Krajewski S, Bodrug S, Krajewska M, et al. Immunohistochemical analysis of Mcl-1 protein in human tissues. Differential regulation of Mcl-1 and Bcl-2 protein production suggests a unique role for Mcl-1 in control of programmed cell death in vivo. Am J Pathol. 1995;146(6):1309–1319.

    CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Reproductive Biomedicine, National Institute of Health and Family Welfare, New Mehrauli Road, Munirka, New Delhi, 110067, India

    Rekha Meena MSc & Man Mohan Misro PhD

  2. Department of Bio-Medical Laboratory Science & Management, Midnapore, West Bengal, India

    Debidas Ghosh PhD

Authors
  1. Rekha Meena MSc
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  2. Man Mohan Misro PhD
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  3. Debidas Ghosh PhD
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Correspondence to Man Mohan Misro PhD.

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Meena, R., Misro, M.M. & Ghosh, D. Complete Sperm Suppression in Rats With Dienogest Plus Testosterone Undecanoate Is Facilitated Through Apoptosis in Testicular Cells. Reprod. Sci. 20, 771–780 (2013). https://doi.org/10.1177/1933719112466305

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