Skip to main content

Advertisement

SpringerLink
Log in

Comparative Effects of Estrogen and Phytoestrogen, Genistein on Testicular Activities of Streptozotocin-Induced Type 2 Diabetic Mice

  • Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

The aim of this study was to compare the effect of synthetic estrogen (E2) with a phytoestrogen and genistein in ameliorating type 2 diabetes mellitus (T2D)-mediated testicular dysfunction in mice. The streptozotocin (STZ)-induced type 2 diabetic mice were treated exogenously with either E2 or genistein for 2 durations and compared their effects on testicular activities, serum glucose, and insulin level. Type 2 diabetic mice treated with E2 for only short term (14 days) improved regressive changes in the testicular histology by increasing testosterone synthesis and improving insulin sensitivity, whereas those treated for longer duration (28 days) failed to improve testicular dysfunctions. On the other hand, genistein treated for both short- and long term was useful in improving T2D-induced adverse effects on testicular functions. This study further suggests that treatment with genistein improves spermatogenesis in type 2 diabetic mice by increasing insulin-induced formation of lactate and antioxidative enzymes, which contributes to prevent germ cell apoptosis. Thus, genistein can be used to ameliorate T2D-induced testicular dysfunction.

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. Ramachandran A, Ma RC, Snehalatha C. Diabetes in Asia. Lancet. 2010;375(9712):408–418.

    Article  PubMed  Google Scholar 

  2. Talaei M, Pan A. Role of phytoestrogens in prevention and management of type 2 diabetes. World J Diabetes. 2015;6(2):271–283.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ray NF, Thamer M, Taylor T, et al. Hospitalization and expenditures for the treatment of general medical conditions among the US diabetic population in 1991. J Clin Endocrinol Metabol. 1996;81(10):3671–3679.

    CAS  Google Scholar 

  4. Baccetti B, La Marca A, Piomboni P, et al Insulin-dependent diabetes in men is associated with hypothalamo-pituitary derangement and with impairment in semen quality. Hum Reprod. 2002;17(10):2673–2677.

    Article  CAS  PubMed  Google Scholar 

  5. Barros RP, Machado UF, Gustafsson JÅ. Estrogen receptors: new players in diabetes mellitus. Trends Mol Med. 2006;12(9):425–431.

    Article  CAS  PubMed  Google Scholar 

  6. Baynes JW, Thorpe SR. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes. 1999;48(1):1–9.

    Article  CAS  PubMed  Google Scholar 

  7. Yu D, Zheng W, Cai H, et al. Long-term diet quality and risk of type 2 diabetes among urban Chinese adults. Diabetes Care. 2017;41(4):723–730.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Alves MG, Martins AD, Rato L, et al. Molecular mechanisms beyond glucose transport in diabetes-related male infertility. Biochim Biophys Acta. 2013;1832(5):626–635.

    Article  CAS  PubMed  Google Scholar 

  9. Meccariello R, Battista N, Bradshaw HB, et al. Updates in reproduction coming from the endocannabinoid system. Int J Endocrinol. 2014;2014:412354.

    PubMed  PubMed Central  Google Scholar 

  10. Pentti K, Tuppurainen MT, Honkanen R, et al. Hormone therapy protects from diabetes: the Kuopio osteoporosis risk factor and prevention study. Eur J Endocrinol. 2009;160(6):979–983.

    Article  CAS  PubMed  Google Scholar 

  11. Kacker R, Traish AM, Morgentaler A. Estrogens in men: clinical implications for sexual function and the treatment of testosterone deficiency. J Sex Med. 2012;9(6):1681–1696.

    Article  CAS  PubMed  Google Scholar 

  12. Le May C, Chu K, Hu M, et al. Estrogens protect pancreatic β-cells from apoptosis and prevent insulin-deficient diabetes mellitus in mice. Proc Natl Acad Sci U S A. 2006;103(24):9232–9237.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Oliveira PF, Alves MG, Rato L, et al. Influence of 5α-dihydrotestosterone and 17β-estradiol on human Sertoli cells metabolism. Int J Androl. 2011;34(6 pt 2):e612–e620.

    Article  CAS  PubMed  Google Scholar 

  14. Cai L, Kang YJ. Oxidative stress and diabetic cardiomyopathy. Cardiovasc Toxicol. 2001;1(3):181–193.

    Article  CAS  PubMed  Google Scholar 

  15. Hamden K, Elfeki A, Ayadi F, et al. Therapeutic effect of phytoecdysteroids rich extract from Ajuga iva on alloxan induced diabetic rats liver, kidney and pancreas. Biofactors. 2008;33(3):165–175.

    Article  CAS  PubMed  Google Scholar 

  16. Long L, Wang J, Lu X, et al. Protective effects of scutellarin on type II diabetes mellitus-induced testicular damages related to reactive oxygen species/Bcl-2/Bax and reactive oxygen species/microcirculation/staving pathway in diabetic rat. J Diabetes Res. 2015;2015:252530.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Davis SR. Phytoestrogen therapy for menopausal symptoms?: there’s no good evidence that it’s any better than placebo. Br Med J. 2001;323(7309):354–355.

    Article  CAS  Google Scholar 

  18. Murkies AL, Wilcox G, Davis SR. Phytoestrogens 1. J Clin Endocrinol Metabol. 1998;83(2):297–303.

    CAS  Google Scholar 

  19. Ososki AL, Kennelly EJ. Phytoestrogens: a review of the present state of research. Phytother Res. 2003;17(8):845–869.

    Article  CAS  PubMed  Google Scholar 

  20. Bhathena SJ, Velasquez MT. Beneficial role of dietary phytoestrogens in obesity and diabetes. Am J Clin Nutr. 2002;76(6):1191–1201.

    Article  CAS  PubMed  Google Scholar 

  21. Behloul N, Wu G. Genistein: a promising therapeutic agent for obesity and diabetes treatment. Eur J Pharmacol. 2013;698(1):31–38.

    Article  CAS  PubMed  Google Scholar 

  22. Shaterzadeh H, Bürger-Mendonça M, Alonso A, et al. The antioxidant effect of genistein on the in vitro metal-mediated formation of free radicals. Clin Biochem. 2011;13(44):S226.

    Article  Google Scholar 

  23. Elmarakby AA, Ibrahim AS, Faulkner J, et al. Tyrosine kinase inhibitor, genistein, reduces renal inflammation and injury in streptozotocin-induced diabetic mice. Vascul Pharmacol. 2011;55(5-6):149–156.

    Article  CAS  PubMed  Google Scholar 

  24. Kwon S, Hess RA, Bunick D, et al. Rooster testicular germ cells and epididymal sperm contain P450 aromatase. Biol Reprod. 1995;53(6):1259–1264.

    Article  CAS  PubMed  Google Scholar 

  25. Reed MJ, Meszaros K, Entes LJ, et al. A new rat model of type 2 diabetes: the fat-fed, streptozotocin-treated rat. Metabolism. 2000;49(11):1390–1394.

    Article  CAS  PubMed  Google Scholar 

  26. Zhang M, Lv XY, Li J, et al. The characterization of high-fat diet and multiple low-dose streptozotocin induced type 2 diabetes rat model. Exp Diabetes Res. 2009;2008:704045.

    PubMed Central  Google Scholar 

  27. Arora S, Ojha SK, Vohora D. Characterisation of streptozotocin induced diabetes mellitus in swiss albino mice. Global J Pharmacol. 2009;3(2):81–84.

    Google Scholar 

  28. Skovsø S. Modeling type 2 diabetes in rats using high fat diet and streptozotocin. J Diabetes Invest. 2014;5(4):349–358.

    Article  CAS  Google Scholar 

  29. Guilford BL, Ryals JM, Lezi E, et al. Dorsal root ganglia mitochondrial biochemical changes in non-diabetic and streptozotocin-induced diabetic mice fed with a standard or high-fat diet. J Neurol Neurosci. 2017;8(2):pii: 180.

    PubMed  PubMed Central  Google Scholar 

  30. Bryzgalova G, Lundholm L, Portwood N, et al. Mechanisms of antidiabetogenic and body weight-lowering effects of estrogen in high-fat diet-fed mice. Am J Physiol Endocrinol Metab. 2008;295(4):E904–E912.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Verma R, Krishna A. Effect of Letrozole, a selective aromatase inhibitor, on testicular activities in adult mice: both in vivo and in vitro study. Gen Comp Endocrinol. 2017;241:57–68.

    Article  CAS  PubMed  Google Scholar 

  32. Russell LD, Ettlin RA, Hikim APS, et al. Histopathology of testis. In: Histological and Histopathological Evaluation of the Testis. Clearwater, FL: Cache River Press; 1990:210–264.

    Google Scholar 

  33. Hess MF, Roser JF. Immunocytochemical localization of cytochrome P450 aromatase in the testis of prepubertal, pubertal, and postpubertal horses. Theriogenology. 2004;61(2-3):293–299.

    Article  CAS  PubMed  Google Scholar 

  34. Narayana K, Al-Bader M, Mousa A, et al. Molecular effects of chemotherapeutic drugs and their modulation by antioxidants in the testis. Eur J Pharmacol. 2012;674(2-3):207–216.

    Article  CAS  PubMed  Google Scholar 

  35. Kilarkaje N, Al-Bader MM. Diabetes-induced oxidative DNA damage alters p53-p21CIP1/Waf1 signaling in the rat testis. Reprod Sci. 2015;22(1):102–112.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Tousson E, Ali EM, Ibrahim W, et al. Proliferating cell nuclear antigen as a molecular biomarker for spermatogenesis in PTU-induced hypothyroidism of rats. Reprod Sci. 2011;18(7):679–686.

    Article  CAS  PubMed  Google Scholar 

  37. Anjum S, Krishna A, Tsutsui K. Inhibitory roles of the mammalian GnIH ortholog RFRP3 in testicular activities in adult mice. J Endocrinol. 2014;223(1):79–91.

    Article  CAS  PubMed  Google Scholar 

  38. Lowry OH, Rosebrough NJ, Farr AL, et al. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193(1):265–275.

    Article  CAS  PubMed  Google Scholar 

  39. Banerjee A, Anjum S, Verma R, Krishna A. Alteration in expression of estrogen receptor isoforms alpha and beta, and aromatase in the testis and its relation with changes in nitric oxide during aging in mice. Steroids. 2012;77(6):609–620.

    Article  CAS  PubMed  Google Scholar 

  40. Van Dijk TH, Laskewitz AJ, Grefhorst A, et al. A novel approach to monitor glucose metabolism using stable isotopically labelled glucose in longitudinal studies in mice. Lab Anim. 2013;47(2):79–88.

    Article  PubMed  CAS  Google Scholar 

  41. Sarkar D, Singh SK. Neonatal hypothyroidism affects testicular glucose homeostasis through increased oxidative stress in prepubertal mice: effects on GLUT3, GLUT8 and Cx43. Andrology. 2017;5(4):749–762.

    Article  CAS  PubMed  Google Scholar 

  42. Tanishima K, Gao SX, Yamamoto R, et al. Biochemical and enzymological study of lactate dehydrogenase isoenzymes from commercial quality control sera and several animal tissue sources. Eur J Clin Chem Clin Biochem. 1995;33(11):865–868.

    CAS  PubMed  Google Scholar 

  43. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979;95(2):351–358.

    Article  CAS  PubMed  Google Scholar 

  44. Das K, Samanta L, Chainy GBN. A modified spectrophotometric assay of superoxide dismutase using nitrite formation by superoxide radicals. Ind J Biochem Biophys. 2000;37:201–204.

    CAS  Google Scholar 

  45. Aebi H. Catalase. In: Bergmeyer HU (Ed.) Methods of Enzymatic Analysis. 2nd ed. 1974;2:673–684.

    Article  Google Scholar 

  46. Lee YS, Cha BY, Saito K, et al. Nobiletin improves hyperglycemia and insulin resistance in obese diabetic ob/ob mice. Biochem Pharmacol. 2010;79(11):1674–1683.

    Article  CAS  PubMed  Google Scholar 

  47. Steger RW, Rabe MB. The effect of diabetes mellitus on endocrine and reproductive function. Proc Soc Exp Biol Med. 1997;214(1):1–10.

    Article  CAS  PubMed  Google Scholar 

  48. Kühn-Velten N, Waldenburger D, Staib W. Evaluation of steroid biosynthetic lesions in isolated leydig cells from the testes of streptozotocin-diabetic rats. Diabetologia. 1982;23(6):529–533.

    Article  PubMed  Google Scholar 

  49. Jones ME, Thorburn AW, Britt KL, et al. Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity. Proc Natl Acad Sci U S A. 2000;97(23):12735–12740.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kianifard D, Sadrkhanlou RA, Hasanzadeh S. The histological, histomorphometrical and histochemical changes of testicular tissue in the metformin treated and untreated streptozotocin-induced adult diabetic rats. Vet Res Forum. 2011;2(1):13–24.

    Google Scholar 

  51. Mäkinen S, Mäkelä S, Weihua Z, et al. Localization of oestrogen receptors alpha and beta in human testis. Mol Hum Reprod. 2001;7(6):497–503.

    Article  PubMed  Google Scholar 

  52. Chieffi P, D’Amato LC, Guarino F, et al. 17β-estradiol induces spermatogonial proliferation through mitogen-activated protein kinase (extracellular signal-regulated kinase 1/2) activity in the lizard (Podarcis s. sicula). Mol Reprod Dev. 2002;61(2):218–225.

    Article  CAS  PubMed  Google Scholar 

  53. Pak TR, Lynch GR, Tsai PS. Estrogen accelerates gonadal recrudescence in photo-regressed male Siberian hamsters. Endocrinol. 2002;143(10):4131–4134.

    Article  CAS  Google Scholar 

  54. O’donnell L., Robertson KM, Jones ME, et al. Estrogen and spermatogenesis. Endocrine Rev. 2001;22(3):289–318.

    Article  Google Scholar 

  55. Nadal A, Alonso-Magdalena P, Soriano S, et al. The pancreatic β-cell as a target of estrogens and xenoestrogens: implications for blood glucose homeostasis and diabetes. Mol Cell Endocrinol. 2009;304(1-2):63–68.

    Article  CAS  PubMed  Google Scholar 

  56. Adlercreutz H, Hämäläinen E, Gorbach S, Goldin B. Dietary phyto-oestrogens and the menopause in Japan. Lancet. 1992;339(8803):1233.

    Article  CAS  PubMed  Google Scholar 

  57. Shanle EK, Hawse JR, Xu W. Generation of stable reporter breast cancer cell lines for the identification of ER subtype selective ligands. Biochem Pharmacol. 2011;82(12):1940–1949.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Aitken RJ, Roman SD. Antioxidant systems and oxidative stress in the testes. Oxid Med Cell Longev. 2008;1(1):15–24.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Gilbert ER, Liu D. Anti-diabetic functions of soy isoflavone genistein: mechanisms underlying its effects on pancreatic β-cell function. Food Funct. 2013;4(2):200–212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Pereira B, Fernando L, Costa RB, et al. Hormonal regulation of superoxide dismutase, catalase, and glutathione peroxidase activities in rat macrophages. Biochem Pharmacol. 1995;50(12):2093–2098.

    Article  CAS  PubMed  Google Scholar 

  61. Rocha CS, Martins AD, Rato L, et al. Melatonin alters the glycolytic profile of Sertoli cells: implications for male fertility. Mol Hum Reprod. 2014;20(11):1067–1076.

    Article  CAS  PubMed  Google Scholar 

  62. Choubey M, Ranjan A, Bora PS, et al. Direct actions of adiponectin on changes in reproductive, metabolic, and anti-oxidative enzymes status in the testis of adult mice. Gen Comp Endocrinol. 2019;279:1–1.

    Article  CAS  PubMed  Google Scholar 

  63. Whitten PL, Naftolin F. Reproductive actions of phytoestrogens. Baillieres Clin Endocrinol Metab. 1998;12(4):667–690.

    Article  CAS  PubMed  Google Scholar 

  64. Huang R, Singh M, Dillon GH. Genistein directly inhibits native and recombinant NMDA receptors. Neuropharmacology. 2010;58(8):1246–1251.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. El-Kordy EA, Alshahrani AM. Effect of genistein, a natural soy isoflavone, on pancreatic β-cells of streptozotocin-induced diabetic rats: histological and immunohistochemical study. J Microsc Ultrastruct. 2015;3(3):108–119.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Oliveira JS, Silva AAN, Silva Junior VA. Phytotherapy in reducing glycemic index and testicular oxidative stress resulting from induced diabetes: a review. Brazilian J Biol. 2017;77(1):68–78.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi, Uttar Pradesh, India

    Rachna Verma PhD

  2. Department of Home Science, Mahila Mahavidyalaya, Banaras Hindu University, Varanasi, Uttar Pradesh, India

    Rusa Samanta MSc

  3. Department of Zoology, Banaras Hindu University, Varanasi, Uttar Pradesh, 221005, India

    Amitabh Krishna PhD

Authors
  1. Rachna Verma PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rusa Samanta MSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amitabh Krishna PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Amitabh Krishna PhD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Verma, R., Samanta, R. & Krishna, A. Comparative Effects of Estrogen and Phytoestrogen, Genistein on Testicular Activities of Streptozotocin-Induced Type 2 Diabetic Mice. Reprod. Sci. 26, 1294–1306 (2019). https://doi.org/10.1177/1933719118815576

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719118815576

Keywords

Search

Navigation