Advertisement

Endocrine

, Volume 55, Issue 2, pp 607–617 | Cite as

New insights for male infertility revealed by alterations in spermatic function and differential testicular expression of thyroid-related genes

  • Renata Marino Romano
  • Samantha Nascimento Gomes
  • Nathalia Carolina Scandolara Cardoso
  • Larissa Schiessl
  • Marco Aurelio Romano
  • Claudio Alvarenga Oliveira
Original Article

Abstract

The impact of thyroid hormone (TH) disorders on male reproductive biology has been a controversial issue for many years. Recently, we reported that hypothyroid male rats have a disruption of the seminiferous epithelium, which may compromise spermatogenesis. To improve the understanding of the reproductive pathogenesis of hypothyroidism and hyperthyroidism, male Wistar rats that developed these dysfunctions in adulthood were used as an experimental model. We evaluated the sperm production, reserves, transit time, morphology, and functionality (acrosome integrity, plasma membrane integrity, and mitochondrial activity), and the testicular expression of the TH receptors (Thra1 and Thra2, Thrb1, and Thrb2), deiodinases (Dio2 and Dio3), and the Mct8 transporter (Slc16a2) were assessed by reverse transcription followed by real-time quantitative PCR (RT-qPCR). The results were evaluated statistically by ANOVA and Tukey HSD test (P < 0.05). Hypothyroidism decreased the total and daily sperm productions and increased the sperm transit time through the epididymis, while the sperm functionality was reduced in both thyroid dysfunctions. Regarding the modulation of gene expression in the testis, hypothyroidism increased the expression of Thra1 and decreased the expression of Dio3, and hyperthyroidism increased the expression of Slc16a2. The observed alterations in spermatic production and function and in the expression of the TH receptor, deiodinase, and the TH transporter are suggestive of TH participation in spermatogenesis in adulthood.

Keywords

Hypothyroidism Hyperthyroidism Sperm production Sperm function Male infertility 

Notes

Acknowledgments

This work was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo—FAPESP, (2014/10845-0), Conselho Nacional de Desenvolvimento Científico e Tecnológico—CNPq (164380/2014-0, 305509/2013-6) and Fundação Araucaria, Brazil.

Compliance with ethical standard

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12020_2016_952_MOESM1_ESM.docx (14 kb)
Supplementary material 1 (DOCX 13 kb)
12020_2016_952_MOESM2_ESM.tif (675 kb)
Supplementary material 2 (TIFF 674 kb)
12020_2016_952_MOESM3_ESM.tif (464 kb)
Supplementary material 3 (TIFF 463 kb)
12020_2016_952_MOESM4_ESM.tif (528 kb)
Supplementary material 4 (TIFF 528 kb)

References

  1. 1.
    S.B. Barker, H.M. Klitgaard, Metabolism of tissues excised from thyroxine-injected rats. Am. J. Physiol. 170(1), 81–86 (1952)PubMedGoogle Scholar
  2. 2.
    E.A. Jannini, S. Ulisse, M. D’Armiento, Thyroid hormone and male gonadal function. Endocr. Rev. 16(4), 443–459 (1995). doi: 10.1210/edrv-16-4-443 PubMedGoogle Scholar
  3. 3.
    J.H. Oppenheimer, H.L. Schwartz, M.I. Surks, Tissue differences in the concentration of triiodothyronine nuclear binding sites in the rat: liver, kidney, pituitary, heart, brain, spleen, and testis. Endocrinology 95(3), 897–903 (1974). doi: 10.1210/endo-95-3-897 CrossRefPubMedGoogle Scholar
  4. 4.
    D.C. Castañeda Cortés, V.S. Langlois, J.I. Fernandino, Crossover of the hypothalamic pituitary-adrenal/interrenal, -thyroid, and -gonadal axes in testicular development. Front. Endocrinol. 5, 139 (2014). doi: 10.3389/fendo.2014.00139 Google Scholar
  5. 5.
    M.S. Wagner, S.M. Wajner, A.L. Maia, The role of thyroid hormone in testicular development and function. J. Endocrinol. 199(3), 351–365 (2008). doi: 10.1677/joe-08-0218 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    G.E. Krassas, K. Poppe, D. Glinoer, Thyroid function and human reproductive health. Endocr. Rev. 31(5), 702–755 (2010). doi: 10.1210/er.2009-0041 CrossRefPubMedGoogle Scholar
  7. 7.
    E. Krajewska-Kulak, P. Sengupta, Thyroid function in male infertility. Front. Endocrinol. 4, 174 (2013). doi: 10.3389/fendo.2013.00174 CrossRefGoogle Scholar
  8. 8.
    P. Donnelly, C. White, Testicular dysfunction in men with primary hypothyroidism; reversal of hypogonadotrophic hypogonadism with replacement thyroxine. Clin. Endocrinol. 52(2), 197–201 (2000)CrossRefGoogle Scholar
  9. 9.
    G.E. Krassas, F. Papadopoulou, K. Tziomalos, T. Zeginiadou, N. Pontikides, Hypothyroidism has an adverse effect on human spermatogenesis: a prospective, controlled study. Thyroid 18(12), 1255–1259 (2008). doi: 10.1089/thy.2008.0257 CrossRefPubMedGoogle Scholar
  10. 10.
    M.R. Nikoobakht, M. Aloosh, N. Nikoobakht, A.R. Mehrsay, F. Biniaz, M.A. Karjalian, The role of hypothyroidism in male infertility and erectile dysfunction. Urol. J. 9(1), 405–409 (2012)PubMedGoogle Scholar
  11. 11.
    G.E. Krassas, N. Pontikides, Male reproductive function in relation with thyroid alterations. Best Pract Res Clin Endocrinol Metab 18(2), 183–195 (2004). doi: 10.1016/j.beem.2004.03.003 CrossRefPubMedGoogle Scholar
  12. 12.
    S. Rojdmark, A. Berg, G. Kallner, Hypothalamic-pituitary-testicular axis in patients with hyperthyroidism. Horm. Res. 29(5–6), 185–190 (1988)PubMedGoogle Scholar
  13. 13.
    R.M. Romano, P. Bargi-Souza, E.L. Brunetto, F. Goulart-Silva, M.C. Avellar, C.A. Oliveira, M.T. Nunes, Hypothyroidism in adult male rats alters posttranscriptional mechanisms of luteinizing hormone biosynthesis. Thyroid 23(4), 497–505 (2013). doi: 10.1089/thy.2011.0514 CrossRefPubMedGoogle Scholar
  14. 14.
    L.B. Smith, W.H. Walker, The regulation of spermatogenesis by androgens. Semin. Cell Dev. Biol. 30, 2–13 (2014). doi: 10.1016/j.semcdb.2014.02.012 CrossRefPubMedGoogle Scholar
  15. 15.
    P.J. O’Shaughnessy, Hormonal control of germ cell development and spermatogenesis. Semin. Cell Dev. Biol. 29, 55–65 (2014). doi: 10.1016/j.semcdb.2014.02.010 CrossRefPubMedGoogle Scholar
  16. 16.
    S.M. Wajner, M. dos Santos Wagner, R.C. Melo, G.G. Parreira, H. Chiarini-Garcia, A.C. Bianco, C. Fekete, E. Sanchez, R.M. Lechan, A.L. Maia, Type 2 iodothyronine deiodinase is highly expressed in germ cells of adult rat testis. J. Endocrinol. 194(1), 47–54 (2007). doi: 10.1677/joe-07-0106 CrossRefPubMedGoogle Scholar
  17. 17.
    A.C. Bianco, G. Anderson, D. Forrest, V.A. Galton, B. Gereben, B.W. Kim, P.A. Kopp, X.H. Liao, M.J. Obregon, R.P. Peeters, S. Refetoff, D.S. Sharlin, W.S. Simonides, R.E. Weiss, G.R. Williams, American Thyroid Association Task Force on, A., Strategies to Investigate Thyroid Hormone, E., Action, American Thyroid Association Guide to investigating thyroid hormone economy and action in rodent and cell models. Thyroid 24(1), 88–168 (2014). doi: 10.1089/thy.2013.0109 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    P. Bargi-Souza, R.M. Romano, M. Salgado Rde, F. Goulart-Silva, E.L. Brunetto, T.M. Zorn, M.T. Nunes, Triiodothyronine rapidly alters the TSH content and the secretory granules distribution in male rat thyrotrophs by a cytoskeleton rearrangement-independent mechanism. Endocrinology 154(12), 4908–4918 (2013). doi: 10.1210/en.2013-1508 CrossRefPubMedGoogle Scholar
  19. 19.
    K.J. Livak, T.D. Schmittgen, Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25(4), 402–408 (2001). doi: 10.1006/meth.2001.1262 CrossRefPubMedGoogle Scholar
  20. 20.
    G.W. Robb, R.P. Amann, G.J. Killian, Daily sperm production and epididymal sperm reserves of pubertal and adult rats. J. Reprod. Fertil. 54(1), 103–107 (1978)CrossRefPubMedGoogle Scholar
  21. 21.
    M.A. Romano, R.M. Romano, L.D. Santos, P. Wisniewski, D.A. Campos, P.B. de Souza, P. Viau, M.M. Bernardi, M.T. Nunes, C.A. de Oliveira, Glyphosate impairs male offspring reproductive development by disrupting gonadotropin expression. Arch. Toxicol. 86(4), 663–673 (2012). doi: 10.1007/s00204-011-0788-9 CrossRefPubMedGoogle Scholar
  22. 22.
    F.T. Mathias, R.M. Romano, M.M. Kizys, T. Kasamatsu, G. Giannocco, M.I. Chiamolera, M.R. Dias-da-Silva, M.A. Romano, Daily exposure to silver nanoparticles during prepubertal development decreases adult sperm and reproductive parameters. Nanotoxicology 9(1), 64–70 (2015). doi: 10.3109/17435390.2014.889237 CrossRefPubMedGoogle Scholar
  23. 23.
    C.E. Pope, Y.Z. Zhang, B.L. Dresser, A simple staining method for quantifying the acrosomal status of cat spermatozoa. Theriogenology 35(1), 257 (1991). doi: 10.1016/0093-691X(91)90233-4 CrossRefGoogle Scholar
  24. 24.
    A. Barth, R. Oko, Abnormal morphology of bovine spermatozoa (Iowa State University Press, Ames, 1989)Google Scholar
  25. 25.
    F. Hrudka, Cytochemical and ultracytochemical demonstration of cytochrome c oxidase in spermatozoa and dynamics of its changes accompanying ageing or induced by stress. Int. J. Androl. 10(6), 809–828 (1987)CrossRefPubMedGoogle Scholar
  26. 26.
    E. Meisami, A. Najafi, P. Timiras, Enhancement of seminiferous tubular growth and spermatogenesis in testes of rats recovering from early hypothyroidism: a quantitative study. Cell Tissue Res. 275(3), 503–511 (1994). doi: 10.1007/BF00318819 CrossRefPubMedGoogle Scholar
  27. 27.
    A.P. Sinha Hikim, R.S. Swerdloff, Hormonal and genetic control of germ cell apoptosis in the testis. Rev. Reprod. 4(1), 38–47 (1999)CrossRefPubMedGoogle Scholar
  28. 28.
    C. Shaha, R. Tripathi, D.P. Mishra, Male germ cell apoptosis: regulation and biology. Philos. Trans. R. Soc. B 365(1546), 1501–1515 (2010). doi: 10.1098/rstb.2009.0124 CrossRefGoogle Scholar
  29. 29.
    S. Chattopadhyay, S. Choudhury, A. Roy, G.B.N. Chainy, L. Samanta, T3 fails to restore mitochondrial thiol redox status altered by experimental hypothyroidism in rat testis. Gen. Comp. Endocrinol. 169(1), 39–47 (2010). doi: 10.1016/j.ygcen.2010.07.014 CrossRefPubMedGoogle Scholar
  30. 30.
    A.R. Chowdhury, A.K. Gautam, B.B. Chatterjee, Thyroid-testis interrelationship during the development and sexual maturity of the rat. Arch. Androl. 13(2–3), 233–239 (1984). doi: 10.3109/01485018408987522 CrossRefPubMedGoogle Scholar
  31. 31.
    H.T. Wan, D.D. Mruk, C.K.C. Wong, C.Y. Cheng, Targeting testis-specific proteins to inhibit spermatogenesis: lesson from endocrine disrupting chemicals. Expert Opin. Ther. Targets 17(7), 839–855 (2013). doi: 10.1517/14728222.2013.791679 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    K. Marchlewska, K. Kula, R. Walczak-Jedrzejowska, E. Oszukowska, S. Orkisz, J. Slowikowska-Hilczer, Triiodothyronine modulates initiation of spermatogenesis in rats depending on treatment timing and blood level of the hormone. Mol. Cell. Endocrinol. 341(1–2), 25–34 (2011). doi: 10.1016/j.mce.2011.04.022 CrossRefPubMedGoogle Scholar
  33. 33.
    C.P. Leblond, Y. Clermont, Definition of the stages of the cycle of the seminiferous epithelium in the rat. Ann. N. Y. Acad. Sci. 55(4), 548–573 (1952)CrossRefPubMedGoogle Scholar
  34. 34.
    W.D. Kempinas, J.D. Suarez, N.L. Roberts, L. Strader, J. Ferrell, J.M. Goldman, G.R. Klinefelter, Rat epididymal sperm quantity, quality, and transit time after guanethidine-induced sympathectomy. Biol. Reprod. 59(4), 890–896 (1998)CrossRefPubMedGoogle Scholar
  35. 35.
    S. Ventura, J.N. Pennefather, Sympathetic co-transmission to the cauda epididymis of the rat: characterization of postjunctional adrenoceptors and purinoceptors. Br. J. Pharmacol. 102(2), 540–544 (1991)CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    B.P. Setchell, W.G. Breed, Chapter 17: anatomy, vasculature, and innervation of the male reproductive tract, in Knobil and Neill’s Physiology of Reproduction, vol. 1, 3rd edn., ed. by J.D. Neill, T.M. Plant, D.W. Pfaff, J.R.G. Challis, D.M. de Kretser, J.S. Richards, P.M. Wassarman (Academic Press, St Louis, 2006), pp. 771–825CrossRefGoogle Scholar
  37. 37.
    J.E. Silva, S.D. Bianco, Thyroid-adrenergic interactions: physiological and clinical implications. Thyroid 18(2), 157–165 (2008). doi: 10.1089/thy.2007.0252 CrossRefPubMedGoogle Scholar
  38. 38.
    H. Preiksaitis, W.H. Kan, G. Kunos, Decreased alpha 1-adrenoceptor responsiveness and density in liver cells of thyroidectomized rats. J. Biol. Chem. 257(8), 4321–4327 (1982)PubMedGoogle Scholar
  39. 39.
    M.M. Cavariani, L.R.A. Kiguti, J.L. Rosa, G.A.A. Leite, P.V. Silva, A.S. Pupo, W.D.G. Kempinas, Bupropion treatment increases epididymal contractility and impairs sperm quality with no effects on the epididymal sperm transit time of male rats. J. Appl. Toxicol. 35(9), 1007–1016 (2015). doi: 10.1002/jat.3089 CrossRefPubMedGoogle Scholar
  40. 40.
    C.S. Borges, G. Missassi, E.S.A. Pacini, L.R.A. Kiguti, M. Sanabria, R.F. Silva, T.P. Banzato, J.E. Perobelli, A.S. Pupo, W.G. Kempinas, Slimmer or fertile? pharmacological mechanisms involved in reduced sperm quality and fertility in rats exposed to the anorexigen sibutramine. PLoS One 8(6), e66091 (2013). doi: 10.1371/journal.pone.0066091 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    M. O’Connell, N. McClure, S.E. Lewis, The effects of cryopreservation on sperm morphology, motility and mitochondrial function. Hum. Reprod. 17(3), 704–709 (2002)CrossRefPubMedGoogle Scholar
  42. 42.
    F.F. Pasqualotto, R.K. Sharma, D.R. Nelson, A.J. Thomas, A. Agarwal, Relationship between oxidative stress, semen characteristics, and clinical diagnosis in men undergoing infertility investigation. Fertil. Steril. 73(3), 459–464 (2000)CrossRefPubMedGoogle Scholar
  43. 43.
    R.J. Aitken, Sperm function tests and fertility. Int. J. Androl. 29(1), 69–75 (2006). doi: 10.1111/j.1365-2605.2005.00630.x. discussion 105–108 CrossRefPubMedGoogle Scholar
  44. 44.
    H. Rodriguez-Martinez, Laboratory semen assessment and prediction of fertility: still utopia? Reprod. Domest. Anim. 38(4), 312–318 (2003)CrossRefPubMedGoogle Scholar
  45. 45.
    T. Rijsselaere, A. Van Soom, S. Tanghe, M. Coryn, D. Maes, A. de Kruif, New techniques for the assessment of canine semen quality: a review. Theriogenology 64(3), 706–719 (2005). doi: 10.1016/j.theriogenology.2005.05.021 CrossRefPubMedGoogle Scholar
  46. 46.
    P. Vernet, R.J. Aitken, J.R. Drevet, Antioxidant strategies in the epididymis. Mol. Cell. Endocrinol. 216(1–2), 31–39 (2004). doi: 10.1016/j.mce.2003.10.069 CrossRefPubMedGoogle Scholar
  47. 47.
    D.K. Sahoo, A. Roy, S. Bhanja, G.B. Chainy, Hypothyroidism impairs antioxidant defence system and testicular physiology during development and maturation. Gen. Comp. Endocrinol. 156(1), 63–70 (2008). doi: 10.1016/j.ygcen.2007.11.007 CrossRefPubMedGoogle Scholar
  48. 48.
    D.K. Sahoo, A. Roy, Compromised rat testicular antioxidant defence system by hypothyroidism before puberty. Int. J. Endocrinol. 2012, 11 (2012). doi: 10.1155/2012/637825 CrossRefGoogle Scholar
  49. 49.
    R.R.M. Maran, Thyroid hormones: their role in testicular steroidogenesis. Syst. Biol. Reprod. Med. 49(5), 375–388 (2003). doi: 10.1080/01485010390204968 Google Scholar
  50. 50.
    D. Canale, M. Agostini, G. Giorgilli, C. Caglieresi, G. Scartabelli, V. Nardini, E.A. Jannini, E. Martino, A. Pinchera, E. Macchia, Thyroid Hormone receptors in neonatal, prepubertal, and adult rat testis. J. Androl. 22(2), 284–288 (2001). doi: 10.1002/j.1939-4640.2001.tb02182.x PubMedGoogle Scholar
  51. 51.
    S. Palmero, P. De Marco, E. Fugassa, Thyroid hormone receptor β mRNA expression in Sertoli cells isolated from prepubertal testis. J. Mol. Endocrinol. 14(1), 131–134 (1995). doi: 10.1677/jme.0.0140131 CrossRefPubMedGoogle Scholar
  52. 52.
    E.A. Jannini, M. Olivieri, S. Francavilla, A. Gulino, E. Ziparo, M. D’Armiento, Ontogenesis of the nuclear 3,5,3’-triiodothyronine receptor in the rat testis. Endocrinology 126(5), 2521–2526 (1990). doi: 10.1210/endo-126-5-2521 CrossRefPubMedGoogle Scholar
  53. 53.
    J.M. Ketelslegers, W.D. Hetzel, R.J. Sherins, K.J. Catt, Developmental changes in testicular gonadotropin receptors: plasma gonadotropins and plasma testosterone in the rat. Endocrinology 103(1), 212–222 (1978). doi: 10.1210/endo-103-1-212 CrossRefPubMedGoogle Scholar
  54. 54.
    A. Chimento, R. Sirianni, I. Casaburi, V. Pezzi, Role of estrogen receptors and G protein-coupled estrogen receptor in regulation of hypothalamus-pituitary-testis axis and spermatogenesis. Front. Endocrinol. 5, 1 (2014). doi: 10.3389/fendo.2014.00001 Google Scholar
  55. 55.
    T.M. Ortiga-Carvalho, A.R. Sidhaye, F.E. Wondisford, Thyroid hormone receptors and resistance to thyroid hormone disorders. Nat. Rev. Endocrinol. 10(10), 582–591 (2014). doi: 10.1038/nrendo.2014.143 CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    M.E. Martinez, A. Karaczyn, J.P. Stohn, W.T. Donnelly, W. Croteau, R.P. Peeters, V.A. Galton, D. Forrest, D. St. Germain, A. Hernandez, The type 3 deiodinase is a critical determinant of appropriate thyroid hormone action in the developing testis. Endocrinology 157(3), 1276–1288 (2016). doi: 10.1210/en.2015-1910 CrossRefPubMedGoogle Scholar
  57. 57.
    W.E. Visser, E.C.H. Friesema, J. Jansen, T.J. Visser, Thyroid hormone transport in and out of cells. Trends Endocrinol. Metab. 19(2), 50–56 (2008). doi: 10.1016/j.tem.2007.11.003 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Renata Marino Romano
    • 1
    • 2
  • Samantha Nascimento Gomes
    • 1
  • Nathalia Carolina Scandolara Cardoso
    • 1
  • Larissa Schiessl
    • 1
  • Marco Aurelio Romano
    • 1
  • Claudio Alvarenga Oliveira
    • 2
  1. 1.Laboratory of Reproductive Toxicology, Department of PharmacyState University of Centro-OesteGuarapuavaBrazil
  2. 2.Department of Animal Reproduction, Faculty of Veterinary MedicineUniversity of Sao PauloSao PauloBrazil

Personalised recommendations