Late-onset hypogonadism in men with type 2 diabetes mellitus and its role in the development of cardiovascular diseases (literature review)

Main Article Content

E.V. Luchytskyy
V.E. Luchytskyi
M.D. Tronko

Abstract

Testosterone is a hormone that plays a key role in carbohydrate, fat and protein metabolism in men. Age-related decrease in testosterone levels, which is facilitated by the development and progression of comorbidities, especially type 2 diabetes mellitus, obesity, dyslipidemia, can have a significant impact on the development of cardiovascular diseases in men and increase the risk of premature death. The paper presents an analysis of modern literature data on the prevalence of late-onset hypogonadism and its impact on the development of cardiovascular pathology in men. An analysis of researches presented in the search database and MedLine database was performed using the keywords “testosterone”, “male”, “late-onset hypogonadism”, and “cardiovascular diseases”. The controversy of a number of hypotheses about the role of androgen deficiency in the development of cardiovascular pathology in men is shown. However, it was determined that most studies showed the correlation between androgen deficiency and the development of metabolic disorders, which are factors for the development of metabolic syndrome, obesity, type 2 diabetes mellitus. In turn, these comorbidities are direct factors that lead to the early onset and progression of vascular pathology and associated mortality in older men. Testosterone therapy is necessary in men with type 2 diabetes mellitus and clinically and laboratory confirmed testosterone deficiency, provided that its safety standards are met. Due to ambiguous results regarding the effect of testosterone on the development of cardiovascular disease, this issue needs further study.

Article Details

How to Cite
Luchytskyy, E., V. Luchytskyi, and M. Tronko. “Late-Onset Hypogonadism in Men With Type 2 Diabetes Mellitus and Its Role in the Development of Cardiovascular Diseases (literature Review)”. INTERNATIONAL JOURNAL OF ENDOCRINOLOGY (Ukraine), vol. 16, no. 6, Oct. 2020, pp. 454-62, doi:10.22141/2224-0721.16.6.2020.215383.
Section
Literature Review

References

Wu FC, Tajar A, Beynon JM, et al; EMAS Group. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med. 2010 Jul 8;363(2):123-35. doi:10.1056/NEJMoa0911101.

Wu FC, Tajar A, Pye SR, et al; European Male Aging Study Group. Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study. J Clin Endocrinol Metab. 2008 Jul;93(7):2737-45. doi:10.1210/jc.2007-1972.

Travison TG, Araujo AB, Kupelian V, O'Donnell AB, McKinlay JB. The relative contributions of aging, health, and lifestyle factors to serum testosterone decline in men. J Clin Endocrinol Metab. 2007 Feb;92(2):549-55. doi:10.1210/jc.2006-1859.

Huhtaniemi I. Late-onset hypogonadism: current concepts and controversies of pathogenesis, diagnosis and treatment. Asian J Androl. 2014 Mar-Apr;16(2):192-202. doi:10.4103/1008-682X.122336.

Luchytsky VYe, Luchytsky YeV, Tron’ko MD. Testosterone replacement therapy in men with type 2 diabetes mellitus with testosterone deficiency syndrome. Endokrynolohiya. 2016;21(4):321-326. (in Ukrainian).

Hofstra J, Loves S, van Wageningen B, Ruinemans-Koerts J, Jansen I, de Boer H. High prevalence of hypogonadotropic hypogonadism in men referred for obesity treatment. Neth J Med. 2008 Mar;66(3):103-9.

Kalyani RR, Dobs AS. Androgen deficiency, diabetes, and the metabolic syndrome in men. Curr Opin Endocrinol Diabetes Obes. 2007 Jun;14(3):226-34. doi:10.1097/MED.0b013e32814db856.

Laaksonen DE, Niskanen L, Punnonen K, et al. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care. 2004 May;27(5):1036-41. doi:10.2337/diacare.27.5.1036.

Choong K, Basaria S. Emerging cardiometabolic complications of androgen deprivation therapy. Aging Male. 2010 Mar;13(1):1-9. doi:10.3109/13685530903410625.

Yao QM, Wang B, An XF, Zhang JA, Ding L. Testosterone level and risk of type 2 diabetes in men: a systematic review and meta-analysis. Endocr Connect. 2018 Jan;7(1):220-231. doi:10.1530/EC-17-0253.

Grossmann M. Testosterone and glucose metabolism in men: current concepts and controversies. J Endocrinol. 2014 Jan 27;220(3):R37-55. doi:10.1530/JOE-13-0393.

Mitsuhashi K, Senmaru T, Fukuda T, et al. Testosterone stimulates glucose uptake and GLUT4 translocation through LKB1/AMPK signaling in 3T3-L1 adipocytes. Endocrine. 2016 Jan;51(1):174-84. doi:10.1007/s12020-015-0666-y.

Chakrabarti P, Kandror KV. The role of mTOR in lipid homeostasis and diabetes progression. Curr Opin Endocrinol Diabetes Obes. 2015 Oct;22(5):340-6. doi:10.1097/MED.0000000000000187.

Haring R, Ittermann T, Völzke H, et al. Prevalence, incidence and risk factors of testosterone deficiency in a population-based cohort of men: results from the study of health in Pomerania. Aging Male. 2010 Dec;13(4):247-57. doi:10.3109/13685538.2010.487553.

Brand JS, van der Tweel I, Grobbee DE, Emmelot-Vonk MH, van der Schouw YT. Testosterone, sex hormone-binding globulin and the metabolic syndrome: a systematic review and meta-analysis of observational studies. Int J Epidemiol. 2011 Feb;40(1):189-207. doi:10.1093/ije/dyq158.

Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract. 2006 Jul;60(7):762-9. doi:10.1111/j.1742-1241.2006.00992.x.

Guzik TJ, Mangalat D, Korbut R. Adipocytokines - novel link between inflammation and vascular function? J Physiol Pharmacol. 2006 Dec;57(4):505-28.

Faris JE, Smith MR. Metabolic sequelae associated with androgen deprivation therapy for prostate cancer. Curr Opin Endocrinol Diabetes Obes. 2010 Jun;17(3):240-6. doi:10.1097/MED.0b013e3283391fd1.

Contreras PH, Serrano FG, Salgado AM, Vigil P. Insulin Sensitivity and Testicular Function in a Cohort of Adult Males Suspected of Being Insulin-Resistant. Front Med (Lausanne). 2018 Jun 26;5:190. doi:10.3389/fmed.2018.00190.

Firtser S, Juonala M, Magnussen CG, et al. Relation of total and free testosterone and sex hormone-binding globulin with cardiovascular risk factors in men aged 24-45 years. The Cardiovascular Risk in Young Finns Study. Atherosclerosis. 2012 May;222(1):257-62. doi:10.1016/j.atherosclerosis.2012.02.020.

Soisson V, Brailly-Tabard S, Empana JP, et al. Low plasma testosterone and elevated carotid intima-media thickness: importance of low-grade inflammation in elderly men. Atherosclerosis. 2012 Jul;223(1):244-9. doi:10.1016/j.atherosclerosis.2012.05.009.

Spitzer M, Huang G, Basaria S, Travison TG, Bhasin S. Risks and benefits of testosterone therapy in older men. Nat Rev Endocrinol. 2013 Jul;9(7):414-24. doi:10.1038/nrendo.2013.73.

Bajos N, Wellings K, Laborde C, Moreau C; CSF Group. Sexuality and obesity, a gender perspective: results from French national random probability survey of sexual behaviours. BMJ. 2010 Jun 15;340:c2573. doi:10.1136/bmj.c2573.

Malavige LS, Levy JC. Erectile dysfunction in diabetes mellitus. J Sex Med. 2009 May;6(5):1232-47. doi:10.1111/j.1743-6109.2008.01168.x.

Saad F. The role of testosterone in type 2 diabetes and metabolic syndrome in men. Arq Bras Endocrinol Metabol. 2009 Nov;53(8):901-7. doi:10.1590/s0004-27302009000800002.

Caronia LM, Dwyer AA, Hayden D, Amati F, Pitteloud N, Hayes FJ. Abrupt decrease in serum testosterone levels after an oral glucose load in men: implications for screening for hypogonadism. Clin Endocrinol (Oxf). 2013 Feb;78(2):291-6. doi:10.1111/j.1365-2265.2012.04486.x.

Hong CY, Park JH, Ahn RS, et al. Molecular mechanism of suppression of testicular steroidogenesis by proinflammatory cytokine tumor necrosis factor alpha. Mol Cell Biol. 2004 Apr;24(7):2593-604. doi:10.1128/mcb.24.7.2593-2604.2004.

Watanobe H, Hayakawa Y. Hypothalamic interleukin-1 beta and tumor necrosis factor-alpha, but not interleukin-6, mediate the endotoxin-induced suppression of the reproductive axis in rats. Endocrinology. 2003 Nov;144(11):4868-75. doi:10.1210/en.2003-0644.

Chistiakov DA, Myasoedova VA, Melnichenko AA, Grechko AV, Orekhov AN. Role of androgens in cardiovascular pathology. Vasc Health Risk Manag. 2018 Oct 15;14:283-290. doi:10.2147/VHRM.S173259.

Torres-Estay V, Carreño DV, San Francisco IF, Sotomayor P, Godoy AS, Smith GJ. Androgen receptor in human endothelial cells. J Endocrinol. 2015 Mar;224(3):R131-7. doi:10.1530/JOE-14-0611.

Flores-Ramírez R, Uribe-Longoria A, Rangel-Fuentes MM, et al. Intracoronary infusion of CD133+ endothelial progenitor cells improves heart function and quality of life in patients with chronic post-infarct heart insufficiency. Cardiovasc Revasc Med. 2010 Apr-Jun;11(2):72-8. doi:10.1016/j.carrev.2009.04.001.

Wang XX, Zhang FR, Shang YP, et al. Transplantation of autologous endothelial progenitor cells may be beneficial in patients with idiopathic pulmonary arterial hypertension: a pilot randomized controlled trial. J Am Coll Cardiol. 2007 Apr 10;49(14):1566-71. doi:10.1016/j.jacc.2006.12.037.

Hill JM, Zalos G, Halcox JP, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med. 2003 Feb 13;348(7):593-600. doi:10.1056/NEJMoa022287.

Yeap BB. Androgens and cardiovascular disease. Curr Opin Endocrinol Diabetes Obes. 2010 Jun;17(3):269-76. doi:10.1097/MED.0b013e3283383031.

Pye SR, Huhtaniemi IT, Finn JD, et al; EMAS Study Group. Late-onset hypogonadism and mortality in aging men. J Clin Endocrinol Metab. 2014 Apr;99(4):1357-66. doi:10.1210/jc.2013-2052.

Hyde Z, Norman PE, Flicker L, et al. Low free testosterone predicts mortality from cardiovascular disease but not other causes: the Health in Men Study. J Clin Endocrinol Metab. 2012 Jan;97(1):179-89. doi:10.1210/jc.2011-1617.

Haring R, Völzke H, Steveling A, et al. Low serum testosterone levels are associated with increased risk of mortality in a population-based cohort of men aged 20-79. Eur Heart J. 2010 Jun;31(12):1494-501. doi:10.1093/eurheartj/ehq009.

Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab. 2008 Jan;93(1):68-75. doi:10.1210/jc.2007-1792.

Lin JW, Lee JK, Wu CK, et al. Metabolic syndrome, testosterone, and cardiovascular mortality in men. J Sex Med. 2011 Aug;8(8):2350-60. doi:10.1111/j.1743-6109.2011.02343.x.

Ruige JB, Mahmoud AM, De Bacquer D, Kaufman JM. Endogenous testosterone and cardiovascular disease in healthy men: a meta-analysis. Heart. 2011 Jun;97(11):870-5. doi:10.1136/hrt.2010.210757.

Schederecker F, Cecil A, Prehn C, et al. Sex hormone-binding globulin, androgens and mortality: the KORA-F4 cohort study. Endocr Connect. 2020 Mar 1;9(4):326–36. doi:10.1530/EC-20-0080.

Kelly DM, Jones TH. Testosterone: a vascular hormone in health and disease. J Endocrinol. 2013 May 7;217(3):R47-71. doi:10.1530/JOE-12-0582.

Araujo AB, Dixon JM, Suarez EA, Murad MH, Guey LT, Wittert GA. Clinical review: Endogenous testosterone and mortality in men: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2011 Oct;96(10):3007-19. doi:10.1210/jc.2011-1137.

Corona G, Rastrelli G, Di Pasquale G, Sforza A, Mannucci E, Maggi M. Endogenous Testosterone Levels and Cardiovascular Risk: Meta-Analysis of Observational Studies. J Sex Med. 2018 Sep;15(9):1260-1271. doi:10.1016/j.jsxm.2018.06.012.

Vikan T, Schirmer H, Njølstad I, Svartberg J. Endogenous sex hormones and the prospective association with cardiovascular disease and mortality in men: the Tromsø Study. Eur J Endocrinol. 2009 Sep;161(3):435-42. doi:10.1530/EJE-09-0284.

Aversa A, Bruzziches R, Francomano D, et al. Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study. J Sex Med. 2010 Oct;7(10):3495-503. doi:10.1111/j.1743-6109.2010.01931.x.

Cunningham GR. Testosterone and metabolic syndrome. Asian J Androl. 2015 Mar-Apr;17(2):192-6. doi:10.4103/1008-682X.148068.

Canguven O, Talib RA, El Ansari W, Yassin DJ, Salman M, Al-Ansari A. Testosterone therapy has positive effects on anthropometric measures, metabolic syndrome components (obesity, lipid profile, Diabetes Mellitus control), blood indices, liver enzymes, and prostate health indicators in elderly hypogonadal men. Andrologia. 2017 Dec;49(10). doi:10.1111/and.12768.

Permpongkosol S, Khupulsup K, Leelaphiwat S, Pavavattananusorn S, Thongpradit S, Petchthong T. Effects of 8-Year Treatment of Long-Acting Testosterone Undecanoate on Metabolic Parameters, Urinary Symptoms, Bone Mineral Density, and Sexual Function in Men With Late-Onset Hypogonadism. J Sex Med. 2016 Aug;13(8):1199-211. doi:10.1016/j.jsxm.2016.06.003.

Yassin AA, Nettleship J, Almehmadi Y, Salman M, Saad F. Effects of continuous long-term testosterone therapy (TTh) on anthropometric, endocrine and metabolic parameters for up to 10 years in 115 hypogonadal elderly men: real-life experience from an observational registry study. Andrologia. 2016 Sep;48(7):793-9. doi:10.1111/and.12514.

Cai X, Tian Y, Wu T, Cao CX, Li H, Wang KJ. Metabolic effects of testosterone replacement therapy on hypogonadal men with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials. Asian J Androl. 2014 Jan-Feb;16(1):146-52. doi:10.4103/1008-682X.122346.

Corona G, Monami M, Rastrelli G, et al. Testosterone and metabolic syndrome: a meta-analysis study. J Sex Med. 2011 Jan;8(1):272-83. doi:10.1111/j.1743-6109.2010.01991.x.

Haddad RM, Kennedy CC, Caples SM, et al. Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc. 2007 Jan;82(1):29-39. doi:10.4065/82.1.29.

Fernández-Balsells MM, Murad MH, Lane M, et al. Clinical review 1: Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2010 Jun;95(6):2560-75. doi:10.1210/jc.2009-2575.

Haider A, Yassin A, Doros G, Saad F. Effects of long-term testosterone therapy on patients with "diabesity": results of observational studies of pooled analyses in obese hypogonadal men with type 2 diabetes. Int J Endocrinol. 2014;2014:683515. doi:10.1155/2014/683515.

Magnussen LV, Glintborg D, Hermann P, Hougaard DM, Højlund K, Andersen M. Effect of testosterone on insulin sensitivity, oxidative metabolism and body composition in aging men with type 2 diabetes on metformin monotherapy. Diabetes Obes Metab. 2016 Oct;18(10):980-9. doi:10.1111/dom.12701.

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 Jan;39(1):82-91. doi:10.2337/dc15-1518.

Pal M, Gupta S. Testosterone supplementation improves glucose homeostasis despite increasing hepatic insulin resistance in male mouse model of type 2 diabetes mellitus. Nutr Diabetes. 2016 Dec 12;6(12):e236. doi:10.1038/nutd.2016.45.

Gianatti EJ, Dupuis P, Hoermann R, et al. Effect of testosterone treatment on glucose metabolism in men with type 2 diabetes: a randomized controlled trial. Diabetes Care. 2014 Aug;37(8):2098-107. doi:10.2337/dc13-2845.

Malkin CJ, Pugh PJ, West JN, van Beek EJ, Jones TH, Channer KS. Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial. Eur Heart J. 2006 Jan;27(1):57-64. doi:10.1093/eurheartj/ehi443.

Caminiti G, Volterrani M, Iellamo F, et al. Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure a double-blind, placebo-controlled, randomized study. J Am Coll Cardiol. 2009 Sep 1;54(10):919-27. doi:10.1016/j.jacc.2009.04.078.

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 Oct 21;169(6):725-33. doi:10.1530/EJE-13-0321.

Baillargeon J, Urban RJ, Kuo YF, et al. Risk of Myocardial Infarction in Older Men Receiving Testosterone Therapy. Ann Pharmacother. 2014 Sep;48(9):1138-1144. doi:10.1177/1060028014539918.

Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab. 2012 Jun;97(6):2050-8. doi:10.1210/jc.2011-2591.

Wu FC. Caveat emptor: does testosterone treatment reduce mortality in men? J Clin Endocrinol Metab. 2012 Jun;97(6):1884-6. doi:10.1210/jc.2012-1977.

Anderson JL, May HT, Lappé DL, et al. Impact of Testosterone Replacement Therapy on Myocardial Infarction, Stroke, and Death in Men With Low Testosterone Concentrations in an Integrated Health Care System. Am J Cardiol. 2016 Mar 1;117(5):794-9. doi:10.1016/j.amjcard.2015.11.063.

Sharma R, Oni OA, Gupta K, et al. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J. 2015 Oct 21;36(40):2706-15. doi:10.1093/eurheartj/ehv346.

Pantalone KM, George J, Ji X, et al. Testosterone replacement therapy and the risk of adverse cardiovascular outcomes and mortality. Basic Clin Androl. 2019 Mar 29;29:5. doi:10.1186/s12610-019-0085-7.

Saboor Aftab SA, Kumar S, Barber TM. The role of obesity and type 2 diabetes mellitus in the development of male obesity-associated secondary hypogonadism. Clin Endocrinol (Oxf). 2013 Mar;78(3):330-7. doi:10.1111/cen.12092.

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