The Complex Relationship Between Erectile Dysfunction and Hypogonadism in Diabetes Mellitus
Purpose of Review
As the prevalence of diabetes mellitus grows worldwide, it is increasingly important to understand the commonly comorbid urologic conditions, hypogonadism and erectile dysfunction, in the setting of the diabetic man. The relationship between the diabetes, hypogonadism, and erectile dysfunction is complex with significant interplay among the disease processes and potential for unique management of the triad. The purpose of this review is to provide an update on the intertwined nature of these diseases in diabetics with special consideration for pathophysiology, diagnosis, and management.
There is a wide range of pathophysiologic mechanisms central to hypogonadism and erectile dysfunction in diabetes mellitus which continue to be identified and better elucidated; nevertheless, metabolic syndrome, composed of insulin resistance, dyslipidemia, hypertension, and obesity, appears to be the common thread between both. An increasing body of evidence suggests that low testosterone is an independent risk factor for cardiovascular disease and worsened overall survival in diabetic men with potential that testosterone therapy may reduce these risks. The treatment of either erectile dysfunction or hypogonadism in diabetic men may also improve the other condition; some evidence suggests that testosterone therapy in hypogonadal diabetics may improve erectile function while daily vardenafil, in addition to improving erectile function, appears to restore hypogonadal diabetics’ testosterone to the eugonadal range.
Metabolic syndrome appears to be the central connection between the increasingly common clinical picture of diabetic men with erectile dysfunction and hypogonadism. The overlapping pathophysiology of these conditions results in unique management considerations.
KeywordsDiabetes mellitus Erectile dysfunction Hypogonadism Testosterone Sexual dysfunction Metabolic syndrome Pathophysiology Management
Compliance with Ethical Standards
Conflict of interest
Dr. Tatem, Dr. Holland, and Dr. Beilan each declare no conflicts of interest. Dr. Lipshultz reports roles with AbbVie as consultant, American Medical Systems as speaker, Aytu Bioscience as consultant, Endo Pharmaceuticals as speaker and consultant, and Lipocine as consultant.
Research Involving Human Participants and/or Animals
This article does not contain any studies with human or animal subjects performed by the author.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.World Health Organization. Global Report on Diabetes. Geneva: WHO Press; 2016.Google Scholar
- 10.Alberti KGMM, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120(16):1640–5. https://doi.org/10.1161/CIRCULATIONAHA.109.192644.CrossRefPubMedGoogle Scholar
- 13.Gandhi J, Dagur G, Warren K, et al. The role of diabetes mellitus in sexual and reproductive health: an overview of pathogenesis, evaluation, and management. Curr Diabetes Rev. 2017;13(6). https://doi.org/10.2174/1573399813666161122124017.
- 22.• Algeffari M, Jayasena CN, MacKeith P, Thapar A, Dhillo WS, Oliver N. Testosterone therapy for sexual dysfunction in men with Type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Diabet Med. 2018;35(2):195–202. https://doi.org/10.1111/dme.13553 A meta-analysis of randomized controlled trials which shows that testosterone therapy may moderately improve erectile function and sexual desire in hypogonadal type 2 diabetics. CrossRefPubMedGoogle Scholar
- 23.•• Santi D, Granata ARM, Guidi A, et al. Six months of daily treatment with vardenafil improves parameters of endothelial inflammation and of hypogonadism in male patients with type 2 diabetes and erectile dysfunction: a randomized, double-blind, prospective trial. Eur J Endocrinol. 2016;174(4):513–22. https://doi.org/10.1530/EJE-15-1100 High-quality trial demonstrating that daily vardenafil improves inflammatory parameters in addition to hypogonadism. CrossRefPubMedGoogle Scholar
- 30.Batty GD, Li Q, Czernichow S, Neal B, Zoungas S, Huxley R, et al. Erectile dysfunction and later cardiovascular disease in men with type 2 diabetes: prospective cohort study based on the ADVANCE trial. J Am Coll Cardiol. 2010;56(23):1908–13. https://doi.org/10.1016/j.jacc.2010.04.067.CrossRefPubMedPubMedCentralGoogle Scholar
- 33.Banks E, Joshy G, Abhayaratna WP, et al. Erectile dysfunction severity as a risk marker for cardiovascular disease hospitalisation and all-cause mortality: a prospective cohort study. PLoS Med. 2013;10(1):e1001372. https://doi.org/10.1371/journal.pmed.1001372.CrossRefPubMedPubMedCentralGoogle Scholar
- 35.Ben Khedher MR, Abid M, Jamoussi K, Hammami M. Comprehensive insight into functional interaction between GNB3 C825T and eNOS T-786C, G894T gene polymorphisms and association with susceptibility to diabetic erectile dysfunction. Andrology. 2018. https://doi.org/10.1111/andr.12543.
- 36.Castela A, Gomes P, Domingues VF, Paíga P, Costa R, Vendeira P, et al. Role of oxidative stress-induced systemic and cavernosal molecular alterations in the progression of diabetic erectile dysfunction. J Diabetes. 2015;7(3):393–401. https://doi.org/10.1111/1753-0407.12181.CrossRefPubMedGoogle Scholar
- 38.Alves-Lopes R, Neves KB, Montezano AC, Harvey A, Carneiro FS, Touyz RM, et al. Internal pudental artery dysfunction in Diabetes mellitus is mediated by NOX1-Derived ROS-, Nrf2-, and rho kinase-dependent mechanisms. Hypertension. 2016;68(4):1056–64. https://doi.org/10.1161/HYPERTENSIONAHA.116.07518.CrossRefPubMedGoogle Scholar
- 40.Alkan E, Ugan RA, Basar MM, et al. Role of endothelin receptors and relationship with nitric oxide synthase in impaired erectile response in diabetic rats. Andrologia. 2017;49(2). https://doi.org/10.1111/and.12607.
- 42.Furukawa S, Sakai T, Niiya T, Miyaoka H, Miyake T, Yamamoto S, et al. Diabetic peripheral neuropathy and prevalence of erectile dysfunction in Japanese patients aged <65 years with type 2 diabetes mellitus: The Dogo Study. Int J Impot Res. 2017;29(1):30–4. https://doi.org/10.1038/ijir.2016.40.CrossRefPubMedGoogle Scholar
- 44.Matsui H, Musicki B, Sopko NA, et al. Early-stage type 2 diabetes mellitus impairs erectile function and neurite outgrowth from the major pelvic ganglion and downregulates the gene expression of neurotrophic factors. Urology. 2017;99:287.e1–7. https://doi.org/10.1016/j.urology.2016.08.045.CrossRefGoogle Scholar
- 45.Hu L, Qi S, Zhang K, Fu Q. Essential role of brain-derived neurotrophic factor (bdnf) in diabetic erectile dysfunction. Andrologia. 2018;50(3). https://doi.org/10.1111/and.12924.
- 48.Yu J, Akishita M, Eto M, Ogawa S, Son BK, Kato S, et al. Androgen receptor-dependent activation of endothelial nitric oxide synthase in vascular endothelial cells: role of phosphatidylinositol 3-kinase/akt pathway. Endocrinology. 2010;151(4):1822–8. https://doi.org/10.1210/en.2009-1048.CrossRefPubMedGoogle Scholar
- 49.Cui K, Li R, Liu K, Wang T, Liu J, Rao K. Testosterone preserves endothelial function through regulation of S1P1/Akt/FOXO3a signalling pathway in the rat corpus cavernosum. Andrologia. 2018:e13173. https://doi.org/10.1111/and.13173.
- 50.Alves-Lopes RU, Neves KB, Silva MA, Olivon VC, Ruginsk SG, Antunes-Rodrigues J, et al. Functional and structural changes in internal pudendal arteries underlie erectile dysfunction induced by androgen deprivation. Asian J Androl. 2017;19(5):526–32. https://doi.org/10.4103/1008-682X.173935.CrossRefPubMedGoogle Scholar
- 60.Cho JW, Duffy JF. Sleep, sleep disorders, and sexual dysfunction. World J Mens Health. 2018. https://doi.org/10.5534/wjmh.180045.
- 62.Tangal S, Ozayar A, Ener K, Gokçe MI, Haliloglu AH. Does mean platelet volume (MPV) have a role in evaluation of erectile dysfunction and its severity? Rev Int Androl. 2018. https://doi.org/10.1016/j.androl.2018.07.007.
- 63.• El Taieb MA, Hegazy EM, Maklad SM, Khairy R. Platelet Indices as a marker for early prediction of erectile dysfunction in diabetic patients. Andrologia. 2019;51(1):e13163. https://doi.org/10.1111/and.13163 Platelet indices may be used to predict diabetic vasculogenic ED.CrossRefPubMedGoogle Scholar
- 64.• Liao X, Qiu S, Bao Y, Wang W, Yang L, Wei Q. Comparative efficacy and safety of phosphodiesterase type 5 inhibitors for erectile dysfunction in diabetic men: a Bayesian network meta-analysis of randomized controlled trials. World J Urol. 2018. https://doi.org/10.1007/s00345-018-2583-1 On-demand vardenafil and mirodenafil may have higher efficacy with lower adverse events in diabetic men than other PDE5i's.
- 65.Buvat J, Montorsi F, Maggi M, Porst H, Kaipia A, Colson MH, et al. Hypogonadal men nonresponders to the PDE5 inhibitor tadalafil benefit from normalization of testosterone levels with a 1% hydroalcoholic testosterone gel in the treatment of erectile dysfunction (TADTEST Study). J Sex Med. 2011;8(1):284–93. https://doi.org/10.1111/j.1743-6109.2010.01956.x.CrossRefPubMedGoogle Scholar
- 67.Hackett G, Cole N, Bhartia M, Kennedy D, Raju J, Wilkinson P, et al. The response to testosterone undecanoate in men with type 2 diabetes is dependent on achieving threshold serum levels (the BLAST study). Int J Clin Pract. 2014;68(2):203–15. https://doi.org/10.1111/ijcp.12235.CrossRefPubMedGoogle Scholar
- 69.Spivak L, Shultz T, Appel B, Verze P, Yagudaev D, Vinarov A. Low-intensity extracorporeal shockwave therapy for erectile dysfunction in diabetic patients. Sex Med Rev. 2019. https://doi.org/10.1016/j.sxmr.2019.06.007.
- 72.SMSNA Position statement on restorative therapies for ED. http://www.smsna.org/V1/about/position-statements. Accessed December 24, 2018.
- 73.Singh R, Artaza JN, Taylor WE, Gonzalez-Cadavid NF, Bhasin S. Androgens stimulate myogenic differentiation and inhibit adipogenesis in C3H 10T1/2 pluripotent cells through an androgen receptor-mediated pathway. Endocrinology. 2003;144(11):5081–8. https://doi.org/10.1210/en.2003-0741.CrossRefPubMedGoogle Scholar
- 76.Isidori AM, Giannetta E, Greco EA, Gianfrilli D, Bonifacio V, Isidori A, et al. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis. Clin Endocrinol. 2005;63(3):280–93. https://doi.org/10.1111/j.1365-2265.2005.02339.x.CrossRefGoogle Scholar
- 77.• Dhindsa S, Ghanim H, Batra M, et al. Insulin resistance and inflammation in hypogonadotropic hypogonadism and their reduction after testosterone replacement in men with type 2 diabetes. Diabetes Care. 2016;39(1):82–91. https://doi.org/10.2337/dc15-1518 After 24 weeks of testosterone therapy, hypogonadal diabetic men had improved insulin sensitivity and body composition. CrossRefPubMedGoogle Scholar
- 85.Bachman E, Travison TG, Basaria S, Davda MN, Guo W, Li M, et al. Testosterone induces erythrocytosis via increased erythropoietin and suppressed hepcidin: evidence for a new erythropoietin/hemoglobin set point. J Gerontol A Biol Sci Med Sci. 2014;69(6):725–35. https://doi.org/10.1093/gerona/glt154.CrossRefPubMedGoogle Scholar
- 88.Daka B, Langer RD, Larsson CA, Rosén T, Jansson PA, Råstam L, et al. Low concentrations of serum testosterone predict acute myocardial infarction in men with type 2 diabetes mellitus. BMC Endocr Disord. 2015;15:35–7. https://doi.org/10.1186/s12902-015-0034-1.CrossRefPubMedPubMedCentralGoogle Scholar
- 90.Muraleedharan V, Marsh H, Kapoor D, Channer KS, Jones TH. Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur J Endocrinol. 2013;169(6):725–33. https://doi.org/10.1530/EJE-13-0321.CrossRefPubMedGoogle Scholar
- 98.Bobjer J, Katrinaki M, Tsatsanis C, Lundberg Giwercman Y, Giwercman A. Negative association between testosterone concentration and inflammatory markers in young men: a nested cross-sectional study. PLoS One. 2013;8(4):e61466. https://doi.org/10.1371/journal.pone.0061466.CrossRefPubMedPubMedCentralGoogle Scholar
- 103.Salvi R, Castillo E, Voirol M-J, et al. Gonadotropin-releasing hormone-expressing neurons immortalized conditionally are activated by insulin: implication of the mitogen-activated protein kinase pathway. Endocrinology. 2006;147(2):816–26. https://doi.org/10.1210/en.2005-0728.CrossRefPubMedGoogle Scholar
- 105.•• Ghanim H, Dhindsa S, Abuaysheh S, et al. Diminished androgen and estrogen receptors and aromatase levels in hypogonadal diabetic men: reversal with testosterone. Eur J Endocrinol. 2018;178(3):277–83. https://doi.org/10.1530/EJE-17-0673 Randomized double-blind placebo-controlled trial demonstrating that hypogonadal diabetics have decreased aromatase, androgen receptor, and estrogen receptor expression rather than the hypothesized compensatory increased expression. This was reversed with testosterone therapy. CrossRefPubMedGoogle Scholar
- 107.Dean JD, McMahon CG, Guay AT, Morgentaler A, Althof SE, Becher EF, et al. The International Society for Sexual Medicine’s process of care for the assessment and management of testosterone deficiency in adult men. J Sex Med. 2015;12(8):1660–86. https://doi.org/10.1111/jsm.12952.CrossRefPubMedGoogle Scholar
- 108.• Hackett G, Heald AH, Sinclair A, Jones PW, Strange RC, Ramachandran S. Serum testosterone, testosterone replacement therapy and all-cause mortality in men with type 2 diabetes: retrospective consideration of the impact of PDE5 inhibitors and statins. Int J Clin Pract. 2016;70(3):244–53. https://doi.org/10.1111/ijcp.12779 Retrospective analysis demonstrating that testosterone therapy was independently associated with decreased mortality in diabetic men. In addition, PDE5i usage was independently associated with reduced mortality regardless of testosterone therapy usage. CrossRefPubMedGoogle Scholar
- 109.•• Hackett G, Cole N, Mulay A, Strange RC, Ramachandran S. Long-term testosterone therapy in type 2 diabetes is associated with reduced mortality without improvement in conventional cardiovascular risk factors. BJU Int. 2019;123(3):519–29. https://doi.org/10.1111/bju.14536 Analysis of men in the BLAST trial demonstrating that long-term testosterone therapy in men with DM2 associated with reduced mortality unrelated to improvement in traditional CVD risk factors. CrossRefPubMedGoogle Scholar
- 110.Contraceptive efficacy of testosterone-induced azoospermia in normal men. World Health Organization Task Force on methods for the regulation of male fertility. Lancet Lond Engl. 1990;336(8721):955–9.Google Scholar
- 114.Wheeler KM, Smith RP, Kumar RA, Setia S, Costabile RA, Kavoussi PK. A comparison of secondary polycythemia in hypogonadal men treated with clomiphene citrate versus testosterone replacement: a multi-institutional study. J Urol. 2017;197(4):1127–31. https://doi.org/10.1016/j.juro.2016.10.068.CrossRefPubMedGoogle Scholar
- 118.Sharma R, Oni OA, Chen G, Sharma M, Dawn B, Sharma R, et al. Association between testosterone replacement therapy and the incidence of DVT and pulmonary embolism: a retrospective cohort study of the Veterans Administration Database. Chest. 2016;150(3):563–71. https://doi.org/10.1016/j.chest.2016.05.007.CrossRefPubMedGoogle Scholar
- 119.Kavoussi PK, Machen GL, Wenzel JL, Ellis AM, Kavoussi M, Kavoussi KM, et al. Medical treatments for hypogonadism do not significantly increase the risk of deep vein thrombosis over general population risk. Urology. 2019;124:127–30. https://doi.org/10.1016/j.urology.2018.11.009.CrossRefPubMedGoogle Scholar
- 121.Tatem AJ, Beilan J, Kovac JR, Lipshultz LI. Management of anabolic steroid-induced infertility: novel strategies for fertility maintenance and recovery. World J Mens Health. 2019. https://doi.org/10.5534/wjmh.190002.
- 122.Pelusi C, Giagulli VA, Baccini M, Fanelli F, Mezzullo M, Fazzini A, et al. Clomiphene citrate effect in obese men with low serum testosterone treated with metformin due to dysmetabolic disorders: a randomized, double-blind, placebo-controlled study. PLoS One. 2017;12(9):e0183369. https://doi.org/10.1371/journal.pone.0183369.CrossRefPubMedPubMedCentralGoogle Scholar
- 125.Habous M, Giona S, Tealab A, Aziz M, Williamson B, Nassar M, et al. Clomiphene citrate and human chorionic gonadotropin are both effective in restoring testosterone in hypogonadism: a short-course randomized study. BJU Int. 2018;122(5):889–97. https://doi.org/10.1111/bju.14401.CrossRefPubMedGoogle Scholar