Skip to main content

Advertisement

SpringerLink
Log in

Nerve Growth Factor Improves the Outcome of Type 2 Diabetes—Induced Hypotestosteronemia and Erectile Dysfunction

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

Abstract

Hypotestosterone and erectile dysfunction (ED) occur frequently in males with type 2 diabetes. It is still clinically challenging to manage diabetes-induced ED. Here, we conducted a 2-arm randomized clinical study and in vitro cell line experiments to investigate the effects of nerve growth factor (NGF) on serum testosterone and ED in diabetic males with sensorimotor polyneuropathy and to identify its underlying mechanisms. The analyses of serum total testosterone (TT) and free testosterone (FT), and 5-item version of the International Index of Erectile Function (IIEF-5) score at baseline and after treatment show increases in TT (3.90 nmol/L, 95% confidence interval [CI]: 3.13–4.66 nmol/L vs 1.21 nmol/L [95% CI: 0.57–1.85 nmol/L]), FT (3.79 pg/mL [95% CI: 3.05–4.54 pg/mL] vs 1.27 pg/mL [95% CI: 0.85–1.70 pg/mL]), and IIEF-5 score (1.84 [95% CI: 1.21–2.47] vs 0.24 [95% CI: −0.24 to 0.73]) in the NGF treatment compared controls (P <.005). In mouse Leydig cells, NGF significantly ameliorated the hyperglycemia-induced downregulation of steroidogenic acute regulatory protein and cytochrome P450 11A1 (P <.05). Thus, NGF treatment effectively improves type 2 diabetes—induced hypotestosterone and ED outcome through a mechanism that includes upregulation of key enzymes in testosterone biosynthesis.

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. Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract. 2014;103(2):137–149.

    Article  CAS  PubMed  Google Scholar 

  2. Yeap BB, Alfonso H, Chubb SA, et al. Reference ranges and determinants of testosterone, dihydrotestosterone, and estradiol levels measured using liquid chromatography-tandem mass spectrometry in a population-based cohort of older men. J Clin Endocrinol Metab. 2012;97(11):4030–4039.

    Article  CAS  PubMed  Google Scholar 

  3. Rao PM, Kelly DM, Jones TH. Testosterone and insulin resistance in the metabolic syndrome and T2DM in men. Nat Rev Endocrinol. 2013;9(8):479–493.

    Article  CAS  PubMed  Google Scholar 

  4. Corona G, Monami M, Rastrelli G, et al. Type 2 diabetes mellitus and testosterone: a meta-analysis study. Int J Androl. 2011;34(6 pt 1):528–540.

    Article  CAS  PubMed  Google Scholar 

  5. Ding EL, Song Y, Malik VS, Liu S. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA. 2006;295(11):1288–1299.

    Article  CAS  PubMed  Google Scholar 

  6. Wang C, Nieschlag E, Swerdloff R, et al. Investigation, treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA and ASA recommendations. Eur J Endocrinol. 2008;159(5):507–514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Buvat J, Maggi M, Gooren L, et al. Endocrine aspects of male sexual dysfunctions. J Sex Med. 2010;7(4 pt 2):1627–1656.

    Article  PubMed  Google Scholar 

  8. Ghazi S, Zohdy W, Elkhiat Y, Shamloul R. Serum testosterone levels in diabetic men with and without erectile dysfunction. Andrologia. 2012;44(6):373–380.

    Article  CAS  PubMed  Google Scholar 

  9. Kapoor D, Clarke S, Channer KS, Jones TH. Erectile dysfunction is associated with low bioactive testosterone levels and visceral adiposity in men with type 2 diabetes. Int J Androl. 2007;30(6):500–507.

    Article  CAS  PubMed  Google Scholar 

  10. Grossmann M, Thomas MC, Panagiotopoulos S, et al. Low testosterone levels are common and associated with insulin resistance in men with diabetes. J Clin Endocrinol Metab. 2008;93(5):1834–1840.

    Article  CAS  PubMed  Google Scholar 

  11. Giagulli VA, Carbone MD, Ramunni MI, et al. Adding liraglutide to lifestyle changes, metformin and testosterone therapy boosts erectile function in diabetic obese men with overt hypogonadism. Andrology. 2015;3(6):1094–1103.

    Article  CAS  PubMed  Google Scholar 

  12. Pelletier G, Li S, Luu-The V, Tremblay Y, Belanger A, Labrie F. Immunoelectron microscopic localization of three key steroidogenic enzymes (cytochrome P450(scc), 3 beta-hydroxysteroid dehydrogenase and cytochrome P450(c17)) in rat adrenal cortex and gonads. J Endocrinol. 2001;171(2):373–383.

    Article  CAS  PubMed  Google Scholar 

  13. Ramalho-Santos J, Amaral S. Mitochondria and mammalian reproduction. Mol Cell Endocrinol. 2013;379(1–2):74–84.

    Article  CAS  PubMed  Google Scholar 

  14. Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane permeabilization in cell death. Physiol Rev. 2007;87(1):99–163.

    Article  CAS  PubMed  Google Scholar 

  15. Shabalina IG, Landreh L, Edgar D, et al. Leydig cell steroidogenesis unexpectedly escapes mitochondrial dysfunction in prematurely aging mice. FASEB J. 2015;29(8):3274–3286.

    Article  CAS  PubMed  Google Scholar 

  16. Hecht MJ, Neundorfer B, Kiesewetter F, Hilz MJ. Neuropathy is a major contributing factor to diabetic erectile dysfunction. Neurol Res. 2001;23(6):651–654.

    Article  CAS  PubMed  Google Scholar 

  17. Bleustein CB, Arezzo JC, Eckholdt H, Melman A. The neuropathy of erectile dysfunction. Int J Impot Res. 2002;14(6):433–439.

    Article  CAS  PubMed  Google Scholar 

  18. Cander S, Coban S, Altuner S, et al. Prevalence and correlates of erectile dysfunction in type 2 diabetes mellitus: a cross-sectional single-center study among Turkish patients. Metab Syndr Relat Disord. 2014;12(6):324–329.

    Article  PubMed  Google Scholar 

  19. Cellek S, Cameron NE, Cotter MA, Muneer A. Pathophysiology of diabetic erectile dysfunction: potential contribution of vasa nervorum and advanced glycation endproducts. Int J Impot Res. 2013;25(1):1–6.

    Article  CAS  PubMed  Google Scholar 

  20. Houtz J, Borden P, Ceasrine A, Minichiello L, Kuruvilla R. Neurotrophin signaling is required for glucose-induced insulin secretion. Dev Cell. 2016;39(3):329–345.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wiesmann C, de Vos AM. Nerve growth factor: structure and function. Cell Mol Life Sci. 2001;58(5–6):748–759.

    Article  CAS  PubMed  Google Scholar 

  22. Davidoff MS, Middendorff R, Enikolopov G, Riethmacher D, Holstein AF, Muller D. Progenitor cells of the testosterone-producing Leydig cells revealed. J Cell Biol. 2004;167(5):935–944.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Muller D, Davidoff MS, Bargheer O, et al. The expression of neurotrophins and their receptors in the prenatal and adult human testis: evidence for functions in Leydig cells. Histochem Cell Biol. 2006;126(2):199–211.

    Article  PubMed  Google Scholar 

  24. Zhao M, Li XY, Xu CY, Zou LP. Efficacy and safety of nerve growth factor for the treatment of neurological diseases: a meta-analysis of 64 randomized controlled trials involving 6,297 patients. Neural Regen Res. 2015;10(5):819–828.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Tesfaye S, Boulton AJ, Dyck PJ, et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010;33(10):2285–2293.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Rosen RC, Cappelleri JC, Smith MD, Lipsky J, Pena BM. Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int J Impot Res. 1999;11(6):319–326.

    Article  CAS  PubMed  Google Scholar 

  27. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412–419.

    Article  CAS  PubMed  Google Scholar 

  28. Thornalley PJ. Glutathione-dependent detoxification of alpha-oxoaldehydes by the glyoxalase system: involvement in disease mechanisms and antiproliferative activity of glyoxalase I inhibitors. Chem Biol Interact. 1998;111–112:137–151.

    Article  PubMed  Google Scholar 

  29. Hales DB, Allen JA, Shankara T, et al. Mitochondrial function in Leydig cell steroidogenesis. Ann N Y Acad Sci. 2005;1061:120–134.

    Article  CAS  PubMed  Google Scholar 

  30. Cameron DF, Rountree J, Schultz RE, Repetta D, Murray FT. Sustained hyperglycemia results in testicular dysfunction and reduced fertility potential in BBWOR diabetic rats. Am J Physiol. 1990;259(6 pt 1):E881–889.

    CAS  PubMed  Google Scholar 

  31. Amaral S, Oliveira PJ, Ramalho-Santos J. Diabetes and the impairment of reproductive function: possible role of mitochondria and reactive oxygen species. Curr Diabetes Rev. 2008;4(1):46–54.

    Article  CAS  PubMed  Google Scholar 

  32. Pittenger G, Vinik A. Nerve growth factor and diabetic neuropathy. Exp Diabesity Res. 2003;4(4):271–285.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Apfel SC. Neurotrophic factors in the therapy of diabetic neuropathy. Am J Med. 1999;107(2B):34S–42S.

    Article  CAS  PubMed  Google Scholar 

  34. Anand P. Neurotrophic factors and their receptors in human sensory neuropathies. Prog Brain Res. 2004;146:477–492.

    Article  CAS  PubMed  Google Scholar 

  35. Sisman AR, Kiray M, Camsari UM, et al. Potential novel biomarkers for diabetic testicular damage in streptozotocin-induced diabetic rats: nerve growth factor beta and vascular endothelial growth factor. Dis Markers. 2014;2014:108106.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Apfel SC. Nerve growth factor for the treatment of diabetic neuropathy: what went wrong, what went right, and what does the future hold? Int Rev Neurobiol. 2002;50:393–413.

    Article  CAS  PubMed  Google Scholar 

  37. Aloe L, Rocco ML, Bianchi P, Manni L. Nerve growth factor: from the early discoveries to the potential clinical use. J Transl Med. 2012;10:239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhang L, Wang H, Yang Y, et al. NGF induces adult stem Leydig cells to proliferate and differentiate during Leydig cell regeneration. Biochem Biophys Res Commun. 2013;436(2):300–305.

    Article  CAS  PubMed  Google Scholar 

  39. Saeednia S, Shabani Nashtaei M, Bahadoran H, Aleyasin A, Amidi F. Effect of nerve growth factor on sperm quality in asthenozoospermic men during cryopreservation. Reprod Biol Endocrinol. 2016;14(1):29.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Endocrinology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 511447, China

    Yixing Wu MD, Fenglian Que MD, Wenxia Xiao MD, Huying Rao MD & Yan Wan RN

  2. Department of Physiology, Guangzhou Medical University, Guangzhou, Guangdong, China

    Chuntao Yang PhD & Fuhui Meng PhD

  3. Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA

    Hugh S. Taylor MD

  4. Department of Chronic Disease Epidemiology, Yale School of Public Health, School of Medicine, Yale Cancer Center, Yale University, New Haven, CT, 06520, USA

    Lingeng Lu MD, PhD

Authors
  1. Yixing Wu MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chuntao Yang PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fuhui Meng PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fenglian Que MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wenxia Xiao MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Huying Rao MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yan Wan RN
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hugh S. Taylor MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lingeng Lu MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yixing Wu MD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, Y., Yang, C., Meng, F. et al. Nerve Growth Factor Improves the Outcome of Type 2 Diabetes—Induced Hypotestosteronemia and Erectile Dysfunction. Reprod. Sci. 26, 386–393 (2019). https://doi.org/10.1177/1933719118773421

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719118773421

Keywords

Search

Navigation