Generic placeholder image

Current Diabetes Reviews

Editor-in-Chief

ISSN (Print): 1573-3998
ISSN (Online): 1875-6417

Review Article

Androgen Therapy in Male Patients Suffering from Type 2 Diabetes: A Review of Benefits and Risks

Author(s): Mortaza F. Hassanabad and Mohammad Fatehi*

Volume 16, Issue 3, 2020

Page: [189 - 199] Pages: 11

DOI: 10.2174/1573399814666180731125724

Price: $65

Abstract

Background: The current estimated numbers of patients with Type 2 Diabetes (T2D) is believed to be close to 10% of the whole populations of many geographical regions, causing serious concerns over the resulting elevated morbidity and mortality as well as the impact on health care systems around the world. In addition to negatively affecting the quality of life, diabetes is associated with cardiovascular and cerebrovascular complications, indicating that appropriate drug therapy should not only deal with metabolic dysfunction but also protect the vascular system, kidney function and skeletal muscle mass from the effects of the epigenetic changes induced by hyperglycaemia.

Objective: To provide an insight into the management of hypogonadism associated with T2D, this review focuses on clinical observations related to androgen therapy in qualified diabetic patients, and discusses the lines of evidence for its benefits and risks. The potential interactions of testosterone with medicines used by patients with T2D will also be discussed.

Conclusion: From recent clinical findings, it became evident that a considerable percentage of patients suffering from T2D manifested low serum testosterone and experienced diminished sexual activity, as well as reduced skeletal muscle mass and lower bone density. Although there are some controversies, Testosterone Replacement Therapy (TRT) for this particular population of patients appears to be beneficial overall only if it is implemented carefully and monitored regularly.

Keywords: Type 2 diabetes, insulin resistance, hypogonadism, testosterone replacement therapy, drug-drug interactions, vascular system.

[1]
International Diabetes Federation. Idf Diabetes Atlas [Internet]. Idf Diabetes Atlas 2015; 1-527. Available from:. http: //www.diabetesatlas.org/resources/2015-atlas
[2]
Q&A. Key points for IDF Diabetes Atlas 2017. Diabetes Res Clin Pract 2018; 135: 235-6.
[http://dx.doi.org/10.1016/j.diabres.2018.01.005] [PMID: 29405943]
[3]
Daousi C, Casson IF, Gill GV, MacFarlane IA, Wilding JPH, Pinkney JH. Prevalence of obesity in type 2 diabetes in secondary care: association with cardiovascular risk factors. Postgrad Med J 2006; 82(966): 280-4.
[http://dx.doi.org/10.1136/pmj.2005.039032] [PMID: 16597817]
[4]
Schwartz SS, Zangeneh F. Evidence-based practice use of quick-release bromocriptine across the natural history of type 2 diabetes mellitus. Postgrad Med 2016; 128(8): 828-38.
[http://dx.doi.org/10.1080/00325481.2016.1214059] [PMID: 27458683]
[5]
Nathan DM, Genuth S, Lachin J, et al. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329(14): 977-86.
[http://dx.doi.org/10.1056/NEJM199309303291401] [PMID: 8366922]
[6]
Gianatti EJ, Hoermann R, Lam Q, Dupuis P, Zajac JD, Grossmann M. Effect of testosterone treatment on cardiac biomarkers in a randomized controlled trial of men with type 2 diabetes. Clin Endocrinol (Oxf) 2016; 84(1): 55-62.
[http://dx.doi.org/10.1111/cen.12842] [PMID: 26120052]
[7]
Tong G, Hua X, Zhong Y, et al. Intensive insulin therapy increases sex hormone-binding globulin in newly diagnosed type 2 diabetic patients. Eur J Endocrinol[Internet] 2014; 170(2): 237-45.
[http://dx.doi.org/10.1530/EJE-13-0557] [PMID: 24194532]
[8]
UK Prospective Diabetes Study. V. Characteristics of newly presenting type 2 diabetic patients: estimated insulin sensitivity and islet 4-cell function. Multi-centre study. Diabet Med 1988; 5(5): 444-8.
[http://dx.doi.org/10.1111/j.1464-5491.1988.tb01025.x] [PMID: 2970917]
[9]
UK Prospective Diabetes Study (UKPDS). VIII. Study design, progress and performance. Diabetologia 1991; 34(12): 877-90.
[http://dx.doi.org/10.1007/BF00400195] [PMID: 1778353]
[10]
Triggle CR, Ding H. Cardiovascular impact of drugs used in the treatment of diabetes. Ther Adv Chronic Dis 2014; 5(6): 245-68.
[http://dx.doi.org/10.1177/2040622314546125] [PMID: 25364492]
[11]
Derosa G, Tinelli C, D’Angelo A, et al. Glyco-metabolic profile among type 2 diabetic patients with erectile dysfunction. Endocr J 2012; 59(7): 611-9.
[http://dx.doi.org/10.1507/endocrj.EJ12-0117] [PMID: 22572549]
[12]
Biswas M, Hampton D, Newcombe RG, Rees DA. Total and free testosterone concentrations are strongly influenced by age and central obesity in men with type 1 and type 2 diabetes but correlate weakly with symptoms of androgen deficiency and diabetes-related quality of life. Clin Endocrinol (Oxf) 2012; 76(5): 665-73.
[http://dx.doi.org/10.1111/j.1365-2265.2011.04196.x] [PMID: 21854402]
[13]
Maggi M, Schulman C, Quinton R, Langham S, Uhl-Hochgraeber K. The burden of testosterone deficiency syndrome in adult men: economic and quality-of-life impact. J Sex Med 2007; 4(4 Pt 1): 1056-69.
[http://dx.doi.org/10.1111/j.1743-6109.2007.00531.x] [PMID: 17627750]
[14]
Rabijewski M, Adamkiewicz M, Zgliczynski S. The influence of testosterone replacement therapy on well-being, bone mineral density and lipids in elderly men. Pol Arch Med Wewn 1998; 100(3): 212.Available from:. http://www.scopus.com/inward/record
[15]
Joshi A, Varthakavi P, Chadha M, Bhagwat N. A study of bone mineral density and its determinants in type 1 diabetes mellitus. J Osteoporos 2013; 2013397814
[http://dx.doi.org/10.1155/2013/397814] [PMID: 23607045]
[16]
Derosa G, Romano D, Tinelli C, D’Angelo A, Maffioli P. Prevalence and associations of erectile dysfunction in a sample of Italian males with type 2 diabetes. Diabetes Res Clin Pract 2015; 108(2): 329-35.
[http://dx.doi.org/10.1016/j.diabres.2015.01.037] [PMID: 25747572]
[17]
Dhindsa S, Reddy A, Karam JS, et al. Prevalence of subnormal testosterone concentrations in men with type 2 diabetes and chronic kidney disease. Eur J Endocrinol 2015; 173(3): 359-66.
[http://dx.doi.org/10.1530/EJE-15-0359] [PMID: 26101371]
[18]
Al Hayek AA, Khader YS, Jafal S, Khawaja N, Robert AA, Ajlouni K. Prevalence of low testosterone levels in men with type 2 diabetes mellitus: a cross-sectional study. J Family Community Med 2013; 20(3): 179-86.
[http://dx.doi.org/10.4103/2230-8229.122006] [PMID: 24672276]
[19]
Pop-Busui R, Boulton AJM, Feldman EL, et al. Diabetic neuropathy: A position statement by the American diabetes association. Diabetes Care 2017; 40(1): 136-54.
[http://dx.doi.org/10.2337/dc16-2042] [PMID: 27999003]
[20]
Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diabetes Care 2003; 26(5): 1553-79.
[http://dx.doi.org/10.2337/diacare.26.5.1553] [PMID: 12716821]
[21]
Penson DF, Wessells H. Erectile dysfunction in diabetic patients. Diabetes Spectr 2004; 17(4): 225-30.
[http://dx.doi.org/10.2337/diaspect.17.4.225]
[22]
Dhindsa S, Prabhakar S, Sethi M, Bandyopadhyay A, Chaudhuri A, Dandona P. Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J Clin Endocrinol Metab 2004; 89(11): 5462-8.
[http://dx.doi.org/10.1210/jc.2004-0804] [PMID: 15531498]
[23]
UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317(7160): 703-13.
[http://dx.doi.org/10.1136/bmj.317.7160.703] [PMID: 9732337]
[24]
Rosen RC, Wu F, Behre HM, et al. RHYME Investigators. Quality of Life and Sexual Function Benefits of Long-Term Testosterone Treatment: Longitudinal Results From the Registry of Hypogonadism in Men (RHYME). J Sex Med 2017; 14(9): 1104-15.
[http://dx.doi.org/10.1016/j.jsxm.2017.07.004] [PMID: 28781213]
[25]
Miner M, Canty DJ, Shabsigh R. Testosterone replacement therapy in hypogonadal men: assessing benefits, risks, and best practices. Postgrad Med 2008; 120(3): 130-53.
[http://dx.doi.org/10.3810/pgm.2008.09.1914] [PMID: 18824832]
[26]
Nigro N, Christ-Crain M. Testosterone treatment in the aging male: myth or reality? Swiss Med Wkly 2012; 142w13539 .
[http://dx.doi.org/10.4414/smw.2012.13539] [PMID: 22430839]
[27]
Goodale T, Sadhu A, Petak S, Robbins R. Testosterone and the Heart. Methodist DeBakey Cardiovasc J 2017; 13(2): 68-72.
[http://dx.doi.org/10.14797/mdcj-13-2-68] [PMID: 28740585]
[28]
Taylor SR, Meadowcraft LM, Williamson B. Prevalence, Pathophysiology, and Management of Androgen Deficiency in Men with Metabolic Syndrome, Type 2 Diabetes Mellitus, or Both. Pharmacotherapy 2015; 35(8): 780-92.
[http://dx.doi.org/10.1002/phar.1623] [PMID: 26289308]
[29]
Stellato RK, Feldman HA, Hamdy O, Horton ES, McKinlay JB. Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study. Diabetes Care 2000; 23(4): 490-4.
[http://dx.doi.org/10.2337/diacare.23.4.490] [PMID: 10857940]
[30]
Gibb FW, Strachan MWJ. Androgen deficiency and type 2 diabetes mellitus. Clin Biochem 2014; 47(10-11): 940-9.
[http://dx.doi.org/10.1016/j.clinbiochem.2014.04.004] [PMID: 24768826]
[31]
Agarwal PK, Singh P, Chowdhury S, et al. A study to evaluate the prevalence of hypogonadism in Indian males with Type-2 diabetes mellitus. Indian J Endocrinol Metab 2017; 21(1): 64-70.
[http://dx.doi.org/10.4103/2230-8210.196008] [PMID: 28217500]
[32]
Kapoor D, Aldred H, Clark S, Channer KS, Jones TH. Clinical and biochemical assessment of hypogonadism in men with type 2 diabetes: correlations with bioavailable testosterone and visceral adiposity. Diabetes Care 2007; 30(4): 911-7.
[http://dx.doi.org/10.2337/dc06-1426] [PMID: 17392552]
[33]
Traish AM, Saad F, Guay A. The dark side of testosterone deficiency: II. Type 2 diabetes and insulin resistance. J Androl 2009; 30(1): 23-32.
[http://dx.doi.org/10.2164/jandrol.108.005751] [PMID: 18772488]
[34]
Rovira-Llopis S, Bañuls C, de Marañon AM, et al. Low testosterone levels are related to oxidative stress, mitochondrial dysfunction and altered subclinical atherosclerotic markers in type 2 diabetic male patients. Free Radic Biol Med 2017; 108: 155-62.
[http://dx.doi.org/10.1016/j.freeradbiomed.2017.03.029] [PMID: 28359952]
[35]
Li Y, Zhang M, Liu X, et al. Correlates and prevalence of hypogonadism in patients with early- and late-onset type 2 diabetes. Andrology 2017; 5(4): 739-43.
[http://dx.doi.org/10.1111/andr.12360] [PMID: 28470687]
[36]
Miyauchi S, Miyake T, Miyazaki M, et al. Free testosterone concentration is inversely associated with markers of liver fibrosis in men with type 2 diabetes mellitus. Endocr J 2017; 64(12): 1137-42.
[http://dx.doi.org/10.1507/endocrj.EJ17-0225] [PMID: 28890481]
[37]
Schianca GPC, Fra GP, Brustia F, et al. Testosterone plasma concentration is associated with insulin resistance in male hypertensive patients. Exp Clin Endocrinol Diabetes 2017; 125(3): 171-5.
[http://dx.doi.org/10.1055/s-0042-121492] [PMID: 28073130]
[38]
Xia JW, Tan SJ, Zhang XL, Jun T, Sun XK, Ling W. Correlation of serum testosterone with insulin resistance in elderly male type 2 diabetes mellitus patients with osteoporosis. J Diabetes Investig 2015; 6(5): 548-52.
[http://dx.doi.org/10.1111/jdi.12291] [PMID: 26417412]
[39]
Madhu SV, Aslam M, Aiman AJ, Siddiqui A, Dwivedi S. Prevalence of hypogonadism in male Type 2 diabetes mellitus patients with and without coronary artery disease. Indian J Endocrinol Metab 2017; 21(1): 31-7.
[http://dx.doi.org/10.4103/2230-8210.195999] [PMID: 28217495]
[40]
Hamilton EJ, Davis WA, Makepeace A, et al. Prevalence and prognosis of a low serum testosterone in men with type 2 diabetes: the Fremantle Diabetes Study Phase II. Clin Endocrinol (Oxf) 2016; 85(3): 444-52.
[http://dx.doi.org/10.1111/cen.13087] [PMID: 27106511]
[41]
Farias JM, Tinetti M, Khoury M, Umpierrez GE. Low testosterone concentration and atherosclerotic disease markers in male patients with type 2 diabetes. J Clin Endocrinol Metab 2014; 99(12): 4698-703.
[http://dx.doi.org/10.1210/jc.2014-2585] [PMID: 25322269]
[42]
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.
[http://dx.doi.org/10.1111/ijcp.12779] [PMID: 26916621]
[43]
Rabijewski M, Papierska L, Piątkiewicz P. The prevalence of prediabetes in population of Polish men with late-onset hypogonadism. Aging Male 2014; 17(3): 141-6.
[http://dx.doi.org/10.3109/13685538.2014.936000] [PMID: 24993355]
[44]
Hassan A, Aburisheh K, Sheikh TJ, Meo SA, Ahmed NA, Al Sharqawi AH. Prevalence of erectile dysfunction among Saudi type 2 diabetic patients. Eur Rev Med Pharmacol Sci 2014; 18(7): 1048-57.
[PMID: 24763886]
[45]
Maseroli E, Corona G, Rastrelli G, et al. Prevalence of endocrine and metabolic disorders in subjects with erectile dysfunction: a comparative study. J Sex Med 2015; 12(4): 956-65.
[http://dx.doi.org/10.1111/jsm.12832] [PMID: 25689116]
[46]
Ye J, Yao Z, Tan A, et al. Low Serum Sex Hormone-Binding Globulin Associated with Insulin Resistance in Men with Nonalcoholic Fatty Liver Disease. Horm Metab Res 2017; 49(5): 359-64.
[http://dx.doi.org/10.1055/s-0043-102690] [PMID: 28282659]
[47]
Cheung KKT, Luk AOY, So WY, et al. Testosterone level in men with type 2 diabetes mellitus and related metabolic effects: A review of current evidence. J Diabetes Investig 2015; 6(2): 112-23.
[http://dx.doi.org/10.1111/jdi.12288] [PMID: 25802717]
[48]
Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 2001; 414(6865): 799-806.
[http://dx.doi.org/10.1038/414799a] [PMID: 11742412]
[49]
Laakso M, Edelman SV, Brechtel G, Baron AD. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance. J Clin Invest 1990; 85(6): 1844-52.
[http://dx.doi.org/10.1172/JCI114644] [PMID: 2189893]
[50]
Del Turco S, Gaggini M, Daniele G, et al. Insulin resistance and endothelial dysfunction: a mutual relationship in cardiometabolic risk. Curr Pharm Des 2013; 19(13): 2420-31.
[http://dx.doi.org/10.2174/1381612811319130010] [PMID: 23173591]
[51]
Boulanger C, Lüscher TF. Release of endothelin from the porcine aorta. Inhibition by endothelium-derived nitric oxide. J Clin Invest 1990; 85(2): 587-90.
[http://dx.doi.org/10.1172/JCI114477] [PMID: 2153712]
[52]
Irving RJ, Noon JP, Watt GC, Webb DJ, Walker BR. Activation of the endothelin system in insulin resistance. QJM 2001; 94(6): 321-6.
[http://dx.doi.org/10.1093/qjmed/94.6.321] [PMID: 11391030]
[53]
Potenza MA, Marasciulo FL, Chieppa DM, et al. Insulin resistance in spontaneously hypertensive rats is associated with endothelial dysfunction characterized by imbalance between NO and ET-1 production. Am J Physiol Heart Circ Physiol 2005; 289(2): H813-22.
[http://dx.doi.org/10.1152/ajpheart.00092.2005] [PMID: 15792994]
[54]
Steinberg HO, Brechtel G, Johnson A, Fineberg N, Baron AD. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release. J Clin Invest 1994; 94(3): 1172-9.
[http://dx.doi.org/10.1172/JCI117433] [PMID: 8083357]
[55]
Li H, Förstermann U. Uncoupling of endothelial NO synthase in atherosclerosis and vascular disease. Curr Opin Pharmacol 2013; 13(2): 161-7.
[http://dx.doi.org/10.1016/j.coph.2013.01.006] [PMID: 23395155]
[56]
Esposito K, Nappo F, Marfella R, et al. Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation 2002; 106(16): 2067-72.
[http://dx.doi.org/10.1161/01.CIR.0000034509.14906.AE] [PMID: 12379575]
[57]
Marette A. Mediators of cytokine-induced insulin resistance in obesity and other inflammatory settings. Curr Opin Clin Nutr Metab Care 2002; 5(4): 377-83.
[http://dx.doi.org/10.1097/00075197-200207000-00005] [PMID: 12107372]
[58]
Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. A role mitochondria NLRP3 inflammasome Act 2011; 469(7329): 221-5.
[59]
Moskovic DJ, Araujo AB, Lipshultz LI, Khera M. The 20-year public health impact and direct cost of testosterone deficiency in U.S. men. J Sex Med 2013; 10(2): 562-9.
[http://dx.doi.org/10.1111/j.1743-6109.2012.02944.x] [PMID: 23035926]
[60]
Arver S, Luong B, Fraschke A, et al. Is testosterone replacement therapy in males with hypogonadism cost-effective? An analysis in Sweden. J Sex Med 2014; 11(1): 262-72.
[http://dx.doi.org/10.1111/jsm.12277] [PMID: 23937088]
[61]
Swerdloff RS, Wang CCL. Review of guidelines on diagnosis and treatment of testosterone deficiency. Testosterone 2012; pp. 408-20.
[http://dx.doi.org/10.1017/CBO9781139003353.019]
[62]
Magnussen LV, Hvid LG, Hermann AP, et al. Testosterone therapy preserves muscle strength and power in aging men with type 2 diabetes-a randomized controlled trial. Andrology 2017; 5(5): 946-53.
[http://dx.doi.org/10.1111/andr.12396] [PMID: 28914503]
[63]
Wang XF, Qu XQ, Zhang TT, Zhang JF. Testosterone suppresses ventricular remodeling and improves left ventricular function in rats following myocardial infarction. Exp Ther Med 2015; 9(4): 1283-91.
[http://dx.doi.org/10.3892/etm.2015.2269] [PMID: 25780423]
[64]
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; 18(10): 980-9.
[http://dx.doi.org/10.1111/dom.12701] [PMID: 27265844]
[65]
S. J. E. G. Effects of testosterone replacement therapy on metabolic disorders in patient with type 2 diabetes mellitus and androgen deficiency. Andrology 2017; 5(Suppl. 1): 76.
[66]
A. H. K.S. H. Effects of long-term testosterone therapy for up to 84 months in hypogonadal men on prostate-related parameters Eur Urol Supp 2015; 14e237.
[http://dx.doi.org/10.1016/S1569-9056(15)60236-6]
[67]
Dhindsa S, Ghanim H, Batra M, et al. Effect of testosterone on hepcidin, ferroportin, ferritin and iron binding capacity in patients with hypogonadotropic hypogonadism and type 2 diabetes. Clin Endocrinol (Oxf) 2016; 85(5): 772-80.
[http://dx.doi.org/10.1111/cen.13130] [PMID: 27292585]
[68]
Grech A, Breck J, Heidelbaugh J. Adverse effects of testosterone replacement therapy: an update on the evidence and controversy. Ther Adv Drug Saf 2014; 5(5): 190-200.
[http://dx.doi.org/10.1177/2042098614548680] [PMID: 25360240]
[69]
Glueck CJ, Fontaine RN, Wang P, et al. Metformin reduces weight, centripetal obesity, insulin, leptin, and low-density lipoprotein cholesterol in nondiabetic, morbidly obese subjects with body mass index greater than 30. Metabolism 2001; 50(7): 856-61.
[http://dx.doi.org/10.1053/meta.2001.24192] [PMID: 11436194]
[70]
Johnson JA, Simpson SH, Toth EL, Majumdar SR. Reduced cardiovascular morbidity and mortality associated with metformin use in subjects with Type 2 diabetes. Diabet Med 2005; 22(4): 497-502.
[http://dx.doi.org/10.1111/j.1464-5491.2005.01448.x] [PMID: 15787679]
[71]
Ajjan RA, Grant PJ. Cardiovascular disease prevention in patients with type 2 diabetes: The role of oral anti-diabetic agents. Diab Vasc Dis Res 2006; 3(3): 147-58.
[http://dx.doi.org/10.3132/dvdr.2006.023] [PMID: 17160909]
[72]
Gangji AS, Cukierman T, Gerstein HC, Goldsmith CH, Clase CM. A systematic review and meta-analysis of hypoglycemia and cardiovascular events: a comparison of glyburide with other secretagogues and with insulin. Diabetes Care 2007; 30(2): 389-94.
[http://dx.doi.org/10.2337/dc06-1789] [PMID: 17259518]
[73]
Cai X, Tian Y, Wu T, Cao C-X, Li H, Wang K-J. 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; 16(1): 146-52.
[http://dx.doi.org/10.4103/1008-682X.122346] [PMID: 24369149]
[74]
Loh RKC, Formosa MF, Eikelis N, et al. Pioglitazone reduces cold-induced brown fat glucose uptake despite induction of browning in cultured human adipocytes: a randomised, controlled trial in humans. Diabetologia 2018; 61(1): 220-30.
[http://dx.doi.org/10.1007/s00125-017-4479-9] [PMID: 29046921]
[75]
Basu A, Charkoudian N, Schrage W, Rizza RA, Basu R, Joyner MJ. Beneficial effects of GLP-1 on endothelial function in humans: dampening by glyburide but not by glimepiride. Am J Physiol Endocrinol Metab 2007; 293(5): E1289-95.
[http://dx.doi.org/10.1152/ajpendo.00373.2007] [PMID: 17711996]
[76]
Egan JM, Chia CW. Incretin therapy and pancreatic pathologies: background pathology versus drug-induced pathology in rats. Diabetes 2014; 63(4): 1174-8.
[http://dx.doi.org/10.2337/db13-1909] [PMID: 24651798]
[77]
Ghosal S, Sinha B. Liraglutide and Dulaglutide therapy in addition to SGLT-2 inhibitor and metformin treatment in Indian type 2 diabetics: a real world retrospective observational study. Clin Diabetes Endocrinol 2018; 4: 11.
[http://dx.doi.org/10.1186/s40842-018-0061-8] [PMID: 29760945]
[78]
Lamers D, Famulla S, Wronkowitz N, et al. Dipeptidyl peptidase 4 is a novel adipokine potentially linking obesity to the metabolic syndrome. Diabetes 2011; 60(7): 1917-25.
[http://dx.doi.org/10.2337/db10-1707] [PMID: 21593202]
[79]
Takasawa W, Ohnuma K, Hatano R, Endo Y, Dang NH, Morimoto C. Inhibition of dipeptidyl peptidase 4 regulates microvascular endothelial growth induced by inflammatory cytokines. Biochem Biophys Res Commun 2010; 401(1): 7-12.
[http://dx.doi.org/10.1016/j.bbrc.2010.08.112] [PMID: 20828536]
[80]
Yamane M, Kawashima K, Yamaguchi K, et al. In vitro profiling of the metabolism and drug-drug interaction of tofogliflozin, a potent and highly specific sodium-glucose co-transporter 2 inhibitor, using human liver microsomes, human hepatocytes, and recombinant human CYP. Xenobiotica 2015; 45(3): 230-8.
[http://dx.doi.org/10.3109/00498254.2014.976296] [PMID: 25350082]
[81]
Saad F. The role of testosterone in type 2 diabetes and metabolic syndrome in men. Arq Bras Endocrinol Metabol 2009; 53(8): 901-7.
[http://dx.doi.org/10.1590/S0004-27302009000800002] [PMID: 20126841]
[82]
Kelly DM, Jones TH. Testosterone: a metabolic hormone in health and disease. J Endocrinol 2013; 217(3): R25-45.
[http://dx.doi.org/10.1530/JOE-12-0455] [PMID: 23378050]
[83]
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.
[http://dx.doi.org/10.1530/EJE-15-1100] [PMID: 26792933]
[84]
Kelly DM, Jones TH. Testosterone and cardiovascular risk in men. Front Horm Res 2014; 43: 1-20.
[PMID: 24943294]
[85]
Krysiak R, Okrzesik J, Okopien B. Different Effects of Metformin on the Hypothalamic-Pituitary-Thyroid Axis in Bromocriptine- and Cabergoline-treated Patients with Hashimoto’s Thyroiditis and Glucose Metabolism Abnormalities. Exp Clin Endocrinol Diabetes 2015; 123(9): 561-6.
[http://dx.doi.org/10.1055/s-0035-1564073] [PMID: 26372847]
[86]
Krysiak R, Gilowski W, Okopień B. The effect of testosterone on cardiovascular risk factors in men with type 2 diabetes and late-onset hypogonadism treated with metformin or glimepiride. Pharmacol Rep 2016; 68(1): 75-9.
[http://dx.doi.org/10.1016/j.pharep.2015.06.003] [PMID: 26721356]
[87]
Bhasin S, Travison TG, Storer TW, et al. Effect of testosterone supplementation with and without a dual 5α-reductase inhibitor on fat-free mass in men with suppressed testosterone production: a randomized controlled trial. JAMA 2012; 307(9): 931-9.
[http://dx.doi.org/10.1001/jama.2012.227] [PMID: 22396515]
[88]
Smith EM, Comiskey CM, Carroll AM. E.M. S. A study of bone mineral density in adults with disability. Arch Phys Med Rehabil 2009; 90(7): 1127-35.
[http://dx.doi.org/10.1016/j.apmr.2008.09.578] [PMID: 19577025]
[89]
Chakrabarty N, Sarkar P, Pal SK, Banerjee R, Sarkar RN, Debnath NB N C. A study of bone mineral density in diabetes mellitus in eastern India J Indian Med Assoc 2004; 102(8): 418-24. 420, 422 passim
[PMID: 15719804]
[90]
Jardí F, Laurent MR, Claessens F, Vanderschueren D. Estradiol and age-related bone loss in men. Physiol Rev 2018; 98(1): 1-1.
[http://dx.doi.org/10.1152/physrev.00051.2017] [PMID: 29167329]
[91]
Dempster DW. The pathophysiology of bone loss. Clin Geriatr Med 2003; 19(2): 259-70. v-vi.
[http://dx.doi.org/10.1016/S0749-0690(02)00098-8 PMID: 12916285]
[92]
Maghbooli Z, Hossein-nezhad A, Khoshniat M, Adibi H, Mohammadzadeh N, Larijani B. A study of bone mineral density in diabetic patients Iran J Public Health 2007; (S): 37-44.
[93]
Dimopoulou C, Ceausu I, Depypere H, et al. EMAS position statement: Testosterone replacement therapy in the aging male‏. Maturitas 2016; 84: 94-9.
[http://dx.doi.org/10.1016/j.maturitas.2015.11.003] [PMID: 26614257]
[94]
Tirabassi G, Biagioli A, Balercia G. Bone benefits of testosterone replacement therapy in male hypogonadism. Panminerva Med 2014; 56(2): 151-63.
[PMID: 24994579]
[95]
Mitkov MD, Aleksandrova IY, Orbetzova MM. Effect of transdermal testosterone or alpha-lipoic acid on erectile dysfunction and quality of life in patients with type 2 diabetes mellitus. Folia Med (Plovdiv) 2013; 55(1): 55-63.
[http://dx.doi.org/10.2478/folmed-2013-0006] [PMID: 23905488]
[96]
Burnett AL, Kan-Dobrosky N, Miller MG. Testosterone replacement with 1% testosterone gel and priapism: no definite risk relationship. J Sex Med 2013; 10(4): 1151-61.
[http://dx.doi.org/10.1111/jsm.12059] [PMID: 23347341]
[97]
Al-Kuraishy HM, Al-Gareeb AI. Erectile dysfunction and low sex drive in men with type 2 DM: The potential role of diabetic pharmacotherapy. J Clin Diagn Res 2016; 10(12): FC21-6.
[http://dx.doi.org/10.7860/JCDR/2016/19971.8996] [PMID: 28208875]
[98]
Costanzo PR, Knoblovits P. Male gonadal axis function in patients with type 2 diabetes. Horm Mol Biol Clin Investig 2016; 26(2): 129-34.
[http://dx.doi.org/10.1515/hmbci-2016-0014] [PMID: 27071157]
[99]
Dhindsa S, Furlanetto R, Vora M, Ghanim H, Chaudhuri A, Dandona P. Low estradiol concentrations in men with subnormal testosterone concentrations and type 2 diabetes. Diabetes Care 2011; 34(8): 1854-9.
[http://dx.doi.org/10.2337/dc11-0208] [PMID: 21715518]
[100]
Giovambattista A, Suescun MO, Nessralla CCDL, França LR, Spinedi E, Calandra RS. Modulatory effects of leptin on leydig cell function of normal and hyperleptinemic rats. Neuroendocrinology 2003; 78(5): 270-9.
[http://dx.doi.org/10.1159/000074448] [PMID: 14657608]
[101]
Gianatti EJ, Dupuis P, Hoermann R, Zajac JD, Grossmann M. Effect of testosterone treatment on constitutional and sexual symptoms in men with type 2 diabetes in a randomized, placebo-controlled clinical trial. J Clin Endocrinol Metab 2014; 99(10): 3821-8.
[http://dx.doi.org/10.1210/jc.2014-1872] [PMID: 24978674]
[102]
Lee CH, Kuo SW, Hung YJ, et al. The effect of testosterone supplement on insulin sensitivity, glucose effectiveness, and acute insulin response after glucose load in male type 2 diabetics. Endocr Res 2005; 31(2): 139-48.
[http://dx.doi.org/10.1080/07435800500320653] [PMID: 16353672]
[103]
Kapoor D, Goodwin E, Channer KS, Jones TH. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol 2006; 154(6): 899-906.
[http://dx.doi.org/10.1530/eje.1.02166] [PMID: 16728551]
[104]
Gopal RA, Bothra N, Acharya SV, et al. Treatment of hypogonadism with testosterone in patients with type 2 diabetes mellitus. Endocr Pract 2010; 16(4): 570-6.
[http://dx.doi.org/10.4158/EP09355.OR] [PMID: 20150021]
[105]
Groti K, Žuran I, Antonič B, Foršnarič L, Pfeifer M. The impact of testosterone replacement therapy on glycemic control, vascular function, and components of the metabolic syndrome in obese hypogonadal men with type 2 diabetes. Aging Male 2018; 21(3): 158-69.
[http://dx.doi.org/10.1080/13685538.2018.1468429] [PMID: 29708829]
[106]
Janjgava S, Zerekidze T, Uchava L, Giorgadze E, Asatiani K. Influence of testosterone replacement therapy on metabolic disorders in male patients with type 2 diabetes mellitus and androgen deficiency. Eur J Med Res 2014; 19: 56.
[http://dx.doi.org/10.1186/s40001-014-0056-6] [PMID: 25338765]
[107]
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; 2014683515
[http://dx.doi.org/10.1155/2014/683515] [PMID: 24738000]
[108]
Shin MJ, Jeon YK, Kim IJ. Testosterone and Sarcopenia. World J Mens Health 2018; 36(3): 192-8.http://www.ncbi.nlm.nih.gov/pubmed/29756416
[http://dx.doi.org/10.5534/wjmh.180001] [PMID: 29756416]
[109]
Spitzer M, Huang G, Basaria S, Travison TG, Bhasin S. Risks and benefits of testosterone therapy in older men. Nat Rev Endocrinol 2013; 9(7): 414-24.
[http://dx.doi.org/10.1038/nrendo.2013.73] [PMID: 23591366]
[110]
Petering RC, Brooks NA. Testosterone therapy: Review of clinical applications. Am Fam Physician [Internet] 2017; 96(7): 441-9.
[PMID: 29094914]
[111]
Jackson G, Nehra A, Miner M, et al. The assessment of vascular risk in men with erectile dysfunction: the role of the cardiologist and general physician. Int J Clin Pract 2013; 67(11): 1163-72.
[http://dx.doi.org/10.1111/ijcp.12200] [PMID: 23714173]
[112]
Corona G, Rastrelli G, Morgentaler A, Sforza A, Mannucci E, Maggi M. Meta-analysis of results of testosterone therapy on sexual function based on international index of erectile function scores. Eur Urol 2017; 72(6): 1000-11.
[http://dx.doi.org/10.1016/j.eururo.2017.03.032] [PMID: 28434676]
[113]
Hackett G, Cole N, Bhartia M, et al. Blast Study Group. 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.
[http://dx.doi.org/10.1111/ijcp.12235] [PMID: 24355040]
[114]
Jones TH, Kelly DM. Randomized controlled trials - mechanistic studies of testosterone and the cardiovascular system. Asian J Androl 2018; 20(2): 120-30.
[http://dx.doi.org/10.4103/aja.aja_6_18] [PMID: 29442075]
[115]
Rolf C, Nieschlag E. Potential adverse effects of long-term testosterone therapy. Baillieres Clin Endocrinol Metab 1998; 12(3): 521-34.
[http://dx.doi.org/10.1016/S0950-351X(98)80305-4] [PMID: 10332571]
[116]
Jones SD Jr, Dukovac T, Sangkum P, Yafi FA, Hellstrom WJG. Erythrocytosis and polycythemia secondary to testosterone replacement therapy in the aging male. Sex Med Rev 2015; 3(2): 101-12.
[http://dx.doi.org/10.1002/smrj.43] [PMID: 27784544]
[117]
Glueck CJ, Wang P. Testosterone therapy, thrombosis, thrombophilia, cardiovascular events. Metabolism 2014; 63(8): 989-94.
[http://dx.doi.org/10.1016/j.metabol.2014.05.005] [PMID: 24930993]
[118]
Glueck CJ, Richardson-Royer C, Schultz R, et al. Testosterone, thrombophilia, and thrombosis. Clin Appl Thromb Hemost 2014; 20(1): 22-30.
[http://dx.doi.org/10.1177/1076029613485154] [PMID: 23615294]
[119]
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): 1094-103.
[http://dx.doi.org/10.1111/andr.12099] [PMID: 26447645]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy