91
Views
0
CrossRef citations to date
0
Altmetric
Review

Cardiovascular safety of testosterone replacement therapy in men: an updated systematic review and meta-analysis

, , , , , , & show all
Pages 565-579 | Received 29 Dec 2023, Accepted 28 Mar 2023, Published online: 06 May 2024

References

  • Harman SM, Metter EJ, Tobin JD, et al. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore longitudinal study of aging. J Clin Endocrinol Metab. 2001 Feb;86(2):724–731.
  • Mohr BA, Guay AT, O’Donnell AB, et al. Normal, bound and nonbound testosterone levels in normally ageing men: results from the Massachusetts male ageing study. Clin Endocrinol (Oxf). 2005 Jan;62(1):64–73.
  • Travison TG, Vesper HW, Orwoll E, et al. Harmonized reference ranges for circulating testosterone levels in men of four cohort studies in the United States and Europe. J Clin Endocrinol Metab. 2017 Apr 1;102(4):1161–1173. doi: 10.1210/jc.2016-2935
  • Tajar A, Forti G, O’Neill TW, et al. Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European male ageing study. J Clin Endocrinol Metab. 2010 Apr;95(4):1810–1818.
  • Corona G, Rastrelli G, Maggi M. Diagnosis and treatment of late-onset hypogonadism: systematic review and meta-analysis of TRT outcomes. Best Pract Res Clin Endocrinol Metab. 2013 Aug;27(4):557–579. doi: 10.1016/j.beem.2013.05.002
  • Handelsman DJ. Androgen misuse and abuse. Endocr Rev. 2021 Jul 16;42(4):457–501.
  • Layton JB, Kim Y, Alexander GC, et al. Association between direct-to-consumer advertising and testosterone testing and initiation in the United States, 2009-2013. JAMA. 2017 Mar 21;317(11):1159–1166. doi: 10.1001/jama.2016.21041
  • FDA drug safety communication FDA cautions about using T products for low T due to aging requires labeling change to inform of possible increased risk of heart attack and stroke with use. 2013 [cited 2023 Oct]. Available from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-cautions-about-using-testosterone-products-low-testosterone-due
  • Corona G, Rastrelli G, Di Pasquale G, et al. Endogenous testosterone levels and cardiovascular risk: meta-analysis of observational studies. J Sex Med. 2018 Sep;15(9):1260–1271.
  • Bhasin S, Brito JP, Cunningham GR, et al. Testosterone therapy in men with hypogonadism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2018 May 1;103(5):1715–1744. doi: 10.1210/jc.2018-00229
  • Yeap BB, Grossmann M, McLachlan RI, et al. Endocrine society of Australia position statement on male hypogonadism (part 1): assessment and indications for testosterone therapy. Med J Aust. 2016 Aug 15;205(4):173–178. doi: 10.5694/mja16.00393
  • Grossmann M, Matsumoto AM. A perspective on middle-aged and older men with functional hypogonadism: focus on holistic management. J Clin Endocrinol Metab. 2017 Mar 1;102(3):1067–1075. doi: 10.1210/jc.2016-3580
  • Snyder PJ, Ellenberg SS, Farrar JT. Testosterone Treatment in Older Men. N Engl J Med. 2016 Jul 7;375(1):90.
  • Wittert G, Bracken K, Robledo KP, et al. Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle programme (T4DM): a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial. Lancet Diabetes Endocrinol. 2021 Jan;9(1):32–45.
  • Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular safety of testosterone-replacement therapy. N Engl J Med. 2023 Jul 13;389(2):107–117. doi: 10.1056/NEJMoa2215025
  • Corona G, Maggi M. Perspective: regulatory agencies’ changes to testosterone product labeling. J Sex Med. 2015 Aug;12(8):1690–1693. doi: 10.1111/jsm.12951
  • Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med. 2010 Jul 8;363(2):109–122. doi: 10.1056/NEJMoa1000485
  • Vigen R, O’Donnell CI, Barón AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013 Nov 6;310(17):1829–1836. doi: 10.1001/jama.2013.280386
  • Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One. 2014;9(1):e85805. doi: 10.1371/journal.pone.0085805
  • PRAC review does not confirm increase in heart problems with testosterone medicines 2014 [cited 2023 Oct]. Available from: https://www.ema.europa.eu/en/news/prac-review-does-not-confirm-increase-heart-problems-testosterone-medicines
  • 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.
  • 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):2560–2575.
  • Ruige JB, Ouwens DM, Kaufman JM. Beneficial and adverse effects of testosterone on the cardiovascular system in men. J Clin Endocrinol Metab. 2013 Nov;98(11):4300–4310. doi: 10.1210/jc.2013-1970
  • Corona G, Maseroli E, Rastrelli G, et al. Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis. Expert Opin Drug Saf. 2014 Oct;13(10):1327–1351.
  • Borst SE, Shuster JJ, Zou B, et al. Cardiovascular risks and elevation of serum DHT vary by route of testosterone administration: a systematic review and meta-analysis. BMC Med. 2014 Nov 27;12(1):211. doi: 10.1186/s12916-014-0211-5
  • Alexander GC, Iyer G, Lucas E, et al. Cardiovascular risks of exogenous testosterone use among men: a systematic review and meta-analysis. Am J Med. 2017 Mar;130(3):293–305.
  • Elliott J, Kelly SE, Millar AC, et al. Testosterone therapy in hypogonadal men: a systematic review and network meta-analysis. BMJ Open. 2017 Nov 16;7(11):e015284.
  • Corona G, Rastrelli G, Di Pasquale G, et al. Testosterone and cardiovascular risk: meta-analysis of interventional studies. J Sex Med.2018 Jun;15(6):820–838.
  • Diem SJ, Greer NL, MacDonald R, et al. Efficacy and safety of testosterone treatment in men: an evidence report for a clinical practice guideline by the American college of physicians. Ann Intern Med. 2020 Jan 21;172(2):105–118. doi: 10.7326/M19-0830
  • Hudson J, Cruickshank M, Quinton R, et al. Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis. Lancet Healthy Longev. 2022 Jun;3(6):e381–e393.
  • Corona G, Rastrelli G, Monami M, et al. Hypogonadism as a risk factor for cardiovascular mortality in men: a meta-analytic study. Eur J Endocrinol. 2011 Nov;165(5):687–701.
  • Gluud C. Testosterone treatment of men with alcoholic cirrhosis: a double-blind study. The Copenhagen study group for liver diseases. Hepatology. 1986 Sep;6(5):807–813. doi: 10.1002/hep.1840060502
  • Drinka PJ, Jochen AL, Cuisinier M, et al. Polycythemia as a complication of testosterone replacement therapy in nursing home men with low testosterone levels. J Am Geriatr Soc. 1995 Aug;43(8):899–901.
  • Aydin S, Odabaş O, Ercan M, et al. Efficacy of testosterone, trazodone and hypnotic suggestion in the treatment of non-organic male sexual dysfunction. Br J Urol. 1996 Feb;77(2):256–260.
  • Hall GM, Larbre JP, Spector TD, et al. A randomized trial of testosterone therapy in males with rheumatoid arthritis. Br J Rheumatol. 1996 Jun;35(6):568–573.
  • Coodley GO, Coodley MK. A trial of testosterone therapy for HIV-associated weight loss. AIDS. 1997 Sep;11(11):1347–1352. doi: 10.1097/00002030-199711000-00008
  • Sih R, Morley JE, Kaiser FE, et al. Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab. 1997 Jun;82(6):1661–1667.
  • Bhasin S, Storer TW, Asbel-Sethi N, et al. Effects of testosterone replacement with a nongenital, transdermal system, Androderm, in human immunodeficiency virus-infected men with low testosterone levels. J Clin Endocrinol Metab. 1998 Sep;83(9):3155–3162.
  • Grinspoon S, Corcoran C, Parlman K, et al. Effects of testosterone and progressive resistance training in eugonadal men with AIDS wasting. A randomized, controlled trial. Ann Intern Med. 2000 Sep 5;133(5):348–355. doi: 10.7326/0003-4819-133-5-200009050-00010
  • Clague JE, Wu FC, Horan MA. Difficulties in measuring the effect of testosterone replacement therapy on muscle function in older men. Int J Androl. 1999 Aug;22(4):261–265. doi: 10.1046/j.1365-2605.1999.00177.x
  • Giorgi A, Weatherby RP, Murphy PW. Muscular strength, body composition and health responses to the use of testosterone enanthate: a double blind study. J Sci Med Sport. 1999 Dec;2(4):341–355. doi: 10.1016/S1440-2440(99)80007-3
  • Snyder PJ, Peachey H, Hannoush P, et al. Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. J Clin Endocrinol Metab. 1999 Aug;84(8):2647–2653.
  • Bhasin S, Storer TW, Javanbakht M, et al. Testosterone replacement and resistance exercise in HIV-infected men with weight loss and low testosterone levels. JAMA. 2000 Feb 9;283(6):763–770. doi: 10.1001/jama.283.6.763
  • English KM, Steeds RP, Jones TH, et al. Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: A randomized, double-blind, placebo-controlled study. Circulation. 2000 Oct 17;102(16):1906–1911. doi: 10.1161/01.CIR.102.16.1906
  • Grinspoon S, Corcoran C, Askari H, et al. Effects of androgen administration in men with the AIDS wasting syndrome. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1998 Jul 1;129(1):18–26. doi: 10.7326/0003-4819-129-1-199807010-00005
  • Rabkin JG, Wagner GJ, Rabkin R. A double-blind, placebo-controlled trial of testosterone therapy for HIV-positive men with hypogonadal symptoms. Arch Gen Psychiatry. 2000 Feb;57(2):141–147. doi: 10.1001/archpsyc.57.2.141 discussion 155-6.
  • Münzer T, Harman SM, Hees P, et al. Effects of GH and/or sex steroid administration on abdominal subcutaneous and visceral fat in healthy aged women and men. J Clin Endocrinol Metab. 2001 Aug;86(8):3604–3610.
  • Howell SJ, Radford JA, Adams JE, et al. Randomized placebo-controlled trial of testosterone replacement in men with mild Leydig cell insufficiency following cytotoxic chemotherapy. Clin Endocrinol (Oxf). 2001 Sep;55(3):315–324.
  • Seidman SN, Spatz E, Rizzo C, et al. Testosterone replacement therapy for hypogonadal men with major depressive disorder: a randomized, placebo-controlled clinical trial. J Clin Psychiatry. 2001 Jun;62(6):406–412.
  • Simon D, Charles MA, Lahlou N, et al. Androgen therapy improves insulin sensitivity and decreases leptin level in healthy adult men with low plasma total testosterone: a 3-month randomized placebo-controlled trial. Diabetes Care. 2001 Dec;24(12):2149–2151.
  • Amory JK, Chansky HA, Chansky KL, et al. Preoperative supraphysiological testosterone in older men undergoing knee replacement surgery. J Am Geriatr Soc. 2002 Oct;50(10):1698–1701.
  • Blackman MR, Sorkin JD, Münzer T, et al. Growth hormone and sex steroid administration in healthy aged women and men: a randomized controlled trial. JAMA. 2002 Nov 13;288(18):2282–2292. doi: 10.1001/jama.288.18.2282
  • Ferrando AA, Sheffield-Moore M, Yeckel CW, et al. Testosterone administration to older men improves muscle function: molecular and physiological mechanisms. Am J Physiol Endocrinol Metab. 2002 Mar;282(3):E601–E607.
  • Liu PY, Yee B, Wishart SM, et al. The short-term effects of high-dose testosterone on sleep, breathing, and function in older men. J Clin Endocrinol Metab. 2003 Aug;88(8):3605–3613.
  • Park NC, Yan BQ, Chung JM, et al. Oral testosterone undecanoate (Andriol) supplement therapy improves the quality of life for men with testosterone deficiency. Aging Male. 2003 Jun;6(2):86–93.
  • Pope HG Jr., Cohane GH, Kanayama G, et al. Testosterone gel supplementation for men with refractory depression: a randomized, placebo-controlled trial. Am J Psychiatry. 2003 Jan;160(1):105–111.
  • Steidle C, Schwartz S, Jacoby K, et al. AA2500 testosterone gel normalizes androgen levels in aging males with improvements in body composition and sexual function. J Clin Endocrinol Metab. 2003 Jun;88(6):2673–2681.
  • Tan RS, Pu SJ. A pilot study on the effects of testosterone in hypogonadal aging male patients with Alzheimer’s disease. Aging Male. 2003 Mar;6(1):13–17. doi: 10.1080/tam.6.1.13.17
  • Amory JK, Watts NB, Easley KA, et al. Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone. J Clin Endocrinol Metab. 2004 Feb;89(2):503–510.
  • Cavallini G, Caracciolo S, Vitali G, et al. Carnitine versus androgen administration in the treatment of sexual dysfunction, depressed mood, and fatigue associated with male aging. Urology. 2004 Apr;63(4):641–646.
  • Kenny AM, Fabregas G, Song C, et al. Effects of testosterone on behavior, depression, and cognitive function in older men with mild cognitive loss. J Gerontol A Biol Sci Med Sci. 2004 Jan;59(1):75–78.
  • Malkin CJ, Pugh PJ, Morris PD, et al. Testosterone replacement in hypogonadal men with angina improves ischaemic threshold and quality of life. Heart. 2004 Aug;90(8):871–876.
  • Malkin CJ, Pugh PJ, Jones RD, et al. The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. J Clin Endocrinol Metab. 2004 Jul;89(7):3313–3318.
  • Rabkin JG, Wagner GJ, McElhiney MC, et al. Testosterone versus fluoxetine for depression and fatigue in HIV/AIDS: a placebo-controlled trial. J Clin Psychopharmacol. 2004 Aug;24(4):379–385.
  • Svartberg J, Aasebø U, Hjalmarsen A, et al. Testosterone treatment improves body composition and sexual function in men with COPD, in a 6-month randomized controlled trial. Respir med. 2004 Sep;98(9):906–913.
  • Seidman SN, Miyazaki M, Roose SP. Intramuscular testosterone supplementation to selective serotonin reuptake inhibitor in treatment-resistant depressed men: randomized placebo-controlled clinical trial. J Clin Psychopharmacol. 2005 Dec;25(6):584–588. doi: 10.1097/01.jcp.0000185424.23515.e5
  • Sullivan DH, Roberson PK, Johnson LE, et al. Effects of muscle strength training and testosterone in frail elderly males. Med Sci Sports Exerc. 2005 Oct;37(10):1664–1672.
  • Brockenbrough AT, Dittrich MO, Page ST, et al. Transdermal androgen therapy to augment EPO in the treatment of anemia of chronic renal disease. Am J Kidney Dis. 2006 Feb;47(2):251–262.
  • Giannoulis MG, Sonksen PH, Umpleby M, et al. The effects of growth hormone and/or testosterone in healthy elderly men: a randomized controlled trial. J Clin Endocrinol Metab. 2006 Feb;91(2):477–484.
  • Gold J, Batterham MJ, Rekers H, et al. Effects of nandrolone decanoate compared with placebo or testosterone on HIV-associated wasting. HIV Med. 2006 Apr;7(3):146–155.
  • Kapoor D, Goodwin E, Channer KS, et al. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol. 2006 Jun;154(6):899–906.
  • Katznelson L, Robinson MW, Coyle CL, et al. Effects of modest testosterone supplementation and exercise for 12 weeks on body composition and quality of life in elderly men. Eur J Endocrinol. 2006 Dec;155(6):867–875.
  • Lu PH, Masterman DA, Mulnard R, et al. Effects of testosterone on cognition and mood in male patients with mild Alzheimer disease and healthy elderly men. Arch Neurol. 2006 Feb;63(2):177–185.
  • Malkin CJ, Pugh PJ, West JN, et al. 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.
  • Marks LS, Mazer NA, Mostaghel E, et al. Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial. JAMA. 2006 Nov 15;296(19):2351–2361. doi: 10.1001/jama.296.19.2351
  • Merza Z, Blumsohn A, Mah PM, et al. Double-blind placebo-controlled study of testosterone patch therapy on bone turnover in men with borderline hypogonadism. Int J Androl. 2006 Jun;29(3):381–391.
  • Nair KS, Rizza RA, O’Brien P, et al. DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med. 2006 Oct 19;355(16):1647–1659. doi: 10.1056/NEJMoa054629
  • Okun MS, Fernandez HH, Rodriguez RL, et al. Testosterone therapy in men with Parkinson disease: results of the TEST-PD Study. Arch Neurol. 2006 May;63(5):729–735.
  • Bhasin S, Parker RA, Sattler F, et al. Effects of testosterone supplementation on whole body and regional fat mass and distribution in human immunodeficiency virus-infected men with abdominal obesity. J Clin Endocrinol Metab. 2007 Mar;92(3):1049–1057.
  • Chiang HS, Hwang TI, Hsui YS, et al. Transdermal testosterone gel increases serum testosterone levels in hypogonadal men in Taiwan with improvements in sexual function. Int J Impot Res. 2007 Jul;19(4):411–417.
  • Agledahl I, Hansen JB, Svartberg J. Impact of testosterone treatment on postprandial triglyceride metabolism in elderly men with subnormal testosterone levels. Scand J Clin Lab Invest. 2008;68(7):641–648. doi: 10.1080/00365510801999068
  • Allan CA, Strauss BJ, Burger HG, et al. Testosterone therapy prevents gain in visceral adipose tissue and loss of skeletal muscle in nonobese aging men. J Clin Endocrinol Metab. 2008 Jan;93(1):139–146.
  • Basurto L, Zarate A, Gomez R, et al. Effect of testosterone therapy on lumbar spine and hip mineral density in elderly men. Aging Male. 2008 Sep;11(3):140–145.
  • Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR, et al. Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial. JAMA. 2008 Jan 2;299(1):39–52. doi: 10.1001/jama.2007.51
  • Knapp PE, Storer TW, Herbst KL, et al. Effects of a supraphysiological dose of testosterone on physical function, muscle performance, mood, and fatigue in men with HIV-associated weight loss. Am J Physiol Endocrinol Metab. 2008 Jun;294(6):E1135–43.
  • Svartberg J, Agledahl I, Figenschau Y, et al. Testosterone treatment in elderly men with subnormal testosterone levels improves body composition and BMD in the hip. Int J Impot Res. 2008 Jul;20(4):378–387.
  • 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):919–927. doi: 10.1016/j.jacc.2009.04.078
  • Chapman IM, Visvanathan R, Hammond AJ, et al. Effect of testosterone and a nutritional supplement, alone and in combination, on hospital admissions in undernourished older men and women. Am J Clin Nutr. 2009 Mar;89(3):880–889.
  • Chiang HS, Cho SL, Lin YC, et al. Testosterone gel monotherapy improves sexual function of hypogonadal men mainly through restoring erection: evaluation by IIEF score. Urology. 2009 Apr;73(4):762–766.
  • Legros JJ, Meuleman EJ, Elbers JM, et al. Oral testosterone replacement in symptomatic late-onset hypogonadism: effects on rating scales and general safety in a randomized, placebo-controlled study. Eur J Endocrinol. 2009 May;160(5):821–831.
  • Mathur A, Malkin C, Saeed B, et al. Long-term benefits of testosterone replacement therapy on angina threshold and atheroma in men. Eur J Endocrinol. 2009 Sep;161(3):443–449.
  • Seidman SN, Orr G, Raviv G, et al. Effects of testosterone replacement in middle-aged men with dysthymia: a randomized, placebo-controlled clinical trial. J Clin Psychopharmacol. 2009 Jun;29(3):216–221.
  • Shores MM, Kivlahan DR, Sadak TI, et al. A randomized, double-blind, placebo-controlled study of testosterone treatment in hypogonadal older men with subthreshold depression (dysthymia or minor depression). J Clin Psychiatry. 2009 Jul;70(7):1009–1016.
  • 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):3495–3503.
  • Aversa A, Bruzziches R, Francomano D, et al. Efficacy and safety of two different testosterone undecanoate formulations in hypogonadal men with metabolic syndrome. J Endocrinol Invest. 2010 Dec;33(11):776–783.
  • Cornoldi A, Caminiti G, Marazzi G, et al. Effects of chronic testosterone administration on myocardial ischemia, lipid metabolism and insulin resistance in elderly male diabetic patients with coronary artery disease. Int J Cardiol. 2010 Jun 25;142(1):50–55. doi: 10.1016/j.ijcard.2008.12.107
  • Gopal RA, Bothra N, Acharya SV, et al. Treatment of hypogonadism with testosterone in patients with type 2 diabetes mellitus. Endocr Pract. 2010 Jul;16(4):570–576.
  • Kalinchenko SY, Tishova YA, Mskhalaya GJ, et al. Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study. Clin Endocrinol (Oxf). 2010 Nov;73(5):602–612.
  • Srinivas-Shankar U, Roberts SA, Connolly MJ, et al. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2010 Feb;95(2):639–650.
  • Amiaz R, Pope HG Jr., Mahne T, et al. Testosterone gel replacement improves sexual function in depressed men taking serotonergic antidepressants: a randomized, placebo-controlled clinical trial. J Sex Marital Ther. 2011;37(4):243–254. doi: 10.1080/0092623X.2011.582425
  • Ho CC, Tong SF, Low WY, et al. A randomized, double-blind, placebo-controlled trial on the effect of long-acting testosterone treatment as assessed by the Aging Male Symptoms scale. BJU Int. 2012 Jul;110(2):260–265.
  • Jones TH, Arver S, Behre HM, et al. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care. 2011 Apr;34(4):828–837.
  • Kaufman JM, Miller MG, Garwin JL, et al. Efficacy and safety study of 1.62% testosterone gel for the treatment of hypogonadal men. J Sex Med. 2011 Jul;8(7):2079–2089.
  • Behre HM, Tammela TL, Arver S, et al. A randomized, double-blind, placebo-controlled trial of testosterone gel on body composition and health-related quality-of-life in men with hypogonadal to low-normal levels of serum testosterone and symptoms of androgen deficiency over 6 months with 12 months open-label follow-up. Aging Male. 2012 Dec;15(4):198–207.
  • Frederiksen L, Højlund K, Hougaard DM, et al. Testosterone therapy increased muscle mass and lipid oxidation in aging men. Age. 2012 Feb;34(1):145–156.
  • Hoyos CM, Yee BJ, Phillips CL, et al. Body compositional and cardiometabolic effects of testosterone therapy in obese men with severe obstructive sleep apnoea: a randomised placebo-controlled trial. Eur J Endocrinol.2012 Oct;167(4):531–541.
  • Hackett G, Cole N, Bhartia M, et al. Testosterone replacement therapy with long-acting testosterone undecanoate improves sexual function and quality-of-life parameters vs. placebo in a population of men with type 2 diabetes. J Sex Med. 2013 Jun;10(6):1612–1627.
  • Hildreth KL, Barry DW, Moreau KL, et al. Effects of testosterone and progressive resistance exercise in healthy, highly functioning older men with low-normal testosterone levels. J Clin Endocrinol Metab. 2013 May;98(5):1891–1900.
  • Maggio M, Snyder PJ, Ceda GP, et al. Is the haematopoietic effect of testosterone mediated by erythropoietin? The results of a clinical trial in older men. Andrology. 2013 Jan;1(1):24–28.
  • Borst SE, Yarrow JF, Conover CF, et al. Musculoskeletal and prostate effects of combined testosterone and finasteride administration in older hypogonadal men: a randomized, controlled trial. Am J Physiol Endocrinol Metab. 2014 Feb 15;306(4):E433–42. doi: 10.1152/ajpendo.00592.2013
  • 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):2098–2107.
  • Janjgava S, Zerekidze T, Uchava L, et al. Influence of testosterone replacement therapy on metabolic disorders in male patients with type 2 diabetes mellitus and androgen deficiency. Eur J Med Res. 2014 Oct 23;19(1):56. doi: 10.1186/s40001-014-0056-6
  • Asih PR, Wahjoepramono EJ, Aniwiyanti V, et al. Testosterone replacement therapy in older male subjective memory complainers: double-blind randomized crossover placebo-controlled clinical trial of physiological assessment and safety. CNS Neurol Disord Drug Targets. 2015;14(5):576–586. doi: 10.2174/1871527314666150429112112
  • Basaria S, Harman SM, Travison TG, et al. Effects of testosterone administration for 3 years on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels: a randomized clinical trial. JAMA. 2015 Aug 11;314(6):570–581. doi: 10.1001/jama.2015.8881
  • Basaria S, Travison TG, Alford D, et al. Effects of testosterone replacement in men with opioid-induced androgen deficiency: a randomized controlled trial. Pain. 2015 Feb;156(2):280–288.
  • Cherrier MM, Anderson K, Shofer J, et al. Testosterone treatment of men with mild cognitive impairment and low testosterone levels. Am J Alzheimers Dis Other Demen. 2015 Jun;30(4):421–430.
  • Glintborg D, Christensen LL, Kvorning T, et al. Differential effects of strength training and testosterone treatment on soluble CD36 in aging men: possible relation to changes in body composition. Scand J Clin Lab Invest. 2015;75(8):659–666.
  • Paduch DA, Polzer PK, Ni X, et al. Testosterone replacement in androgen-deficient men with ejaculatory dysfunction: a randomized controlled trial. J Clin Endocrinol Metab. 2015 Aug;100(8):2956–2962.
  • Brock G, Heiselman D, Maggi M, et al. Effect of testosterone solution 2% on testosterone concentration, sex drive and energy in hypogonadal men: results of a placebo controlled study. J Urol. 2016 Mar;195(3):699–705.
  • 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.
  • Magnussen LV, Glintborg D, Hermann P, et al. Effect of testosterone on insulin sensitivity, oxidative metabolism and body composition in aging men with type 2 diabetes on metformin monotherapy. Diab Obes Metab. 2016 Oct;18(10):980–989.
  • Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of testosterone treatment in older men. N Engl J Med. 2016 Feb 18;374(7):611–624. doi: 10.1056/NEJMoa1506119
  • Budoff MJ, Ellenberg SS, Lewis CE, et al. Testosterone treatment and coronary artery plaque volume in older men with low testosterone. JAMA. 2017 Feb 21;317(7):708–716. doi: 10.1001/jama.2016.21043
  • Chillarón JJ, Fernández-Miró M, Albareda M, et al. Testosterone undecanoate improves lipid profile in patients with type 1 diabetes and hypogonadotrophic hypogonadism. Endocr J. 2016 Sep 30;63(9):849–855. doi: 10.1507/endocrj.EJ16-0195
  • Groti K, Žuran I, Antonič B, et al. 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 Sep;21(3):158–169.
  • Inoue Y, Nakamura K, Kuwahara Y, et al. Efficacy of testosterone treatment in hemodialysis patients as assessed by aging males’ symptoms scores: a pilot study. Am J Mens Health. 2018 Sep;12(5):1541–1547.
  • Navarro-Peñalver M, Perez-Martinez MT, Gómez-Bueno M, et al. Testosterone replacement therapy in deficient patients with chronic heart failure: a randomized double-blind controlled pilot study. J Cardiovasc Pharmacol Ther. 2018 Nov;23(6):543–550.
  • Walsh JS, Marshall H, Smith IL, et al. Testosterone replacement in young male cancer survivors: a 6-month double-blind randomised placebo-controlled trial. PLOS Med. 2019 Nov;16(11):e1002960.
  • Mok SF, Fennell C, Savkovic S, et al. Testosterone for androgen deficiency-like symptoms in men without pathologic hypogonadism: a randomized, placebo-controlled cross-over with masked choice extension clinical trial. J Gerontol A Biol Sci Med Sci. 2020 Sep 16;75(9):1723–1731. doi: 10.1093/gerona/glz195
  • Barnouin Y, Armamento-Villareal R, Celli A, et al. Testosterone replacement therapy added to intensive lifestyle intervention in older men with obesity and hypogonadism. J Clin Endocrinol Metab. 2021 Mar 8;106(3):e1096–e1110. doi: 10.1210/clinem/dgaa917
  • Kolind MI, Christensen LL, Caserotti P, et al. Muscle function following testosterone replacement in men on opioid therapy for chronic non-cancer pain: A randomized controlled trial. Andrology. 2022 Mar;10(3):551–559.
  • Kreiberg M, Jørgensen N, Juul A, et al. A randomized double-blind single center study of testosterone replacement therapy or placebo in testicular cancer survivors with mild Leydig cell insufficiency (Einstein-intervention). Clin Genitourin Cancer. 2022 Oct;20(5):404–414.
  • Connor SG, Fairchild TJ, Learmonth YC, et al. Testosterone treatment combined with exercise to improve muscle strength, physical function and quality of life in men affected by inclusion body myositis: a randomised, double-blind, placebo-controlled, crossover trial. PLoS One. 2023;18(4):e0283394. doi: 10.1371/journal.pone.0283394
  • Magnani JW, Moser CB, Murabito JM, et al. Association of sex hormones, aging, and atrial fibrillation in men: the Framingham heart study. Circ Arrhythm Electrophysiol. 2014 Apr;7(2):307–312.
  • O’Neal WT, Nazarian S, Alonso A, et al. Sex hormones and the risk of atrial fibrillation: The Multi-Ethnic Study of Atherosclerosis (MESA). Endocrine. 2017 Oct;58(1):91–96.
  • Zeller T, Schnabel RB, Appelbaum S, et al. Low testosterone levels are predictive for incident atrial fibrillation and ischaemic stroke in men, but protective in women - results from the FINRISK study. Eur J Prev Cardiol. 2018 Jul;25(11):1133–1139.
  • Berger D, Folsom AR, Schreiner PJ, et al. Plasma total testosterone and risk of incident atrial fibrillation: the atherosclerosis risk in communities (ARIC) study. Maturitas. 2019 Jul;125:5–10. doi: 10.1016/j.maturitas.2019.03.015
  • Xu B, Mo W, Tan X, et al. Insulin-like growth factor 1 and risk of cardiovascular disease: results from the UK biobank cohort study. J Clin Endocrinol Metab. 2023 Sep 4;108(9):e850–e860. doi: 10.1210/clinem/dgad105
  • Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011 Oct 18;343(oct18 2):d5928. doi: 10.1136/bmj.d5928
  • Wells GA, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses [cited 2023 Oct]. Available from: https://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
  • Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994 Dec;50(4):1088–1101. doi: 10.2307/2533446
  • Saad F, Caliber M, Doros G, et al. Long-term treatment with testosterone undecanoate injections in men with hypogonadism alleviates erectile dysfunction and reduces risk of major adverse cardiovascular events, prostate cancer, and mortality. Aging Male. 2020 Mar;23(1):81–92.
  • Haider A, Yassin A, Haider KS, et al. Men with testosterone deficiency and a history of cardiovascular diseases benefit from long-term testosterone therapy: observational, real-life data from a registry study. Vasc Health Risk Manag. 2016;12:251–261. doi: 10.2147/VHRM.S108947
  • Corona G, Vena W, Pizzocaro A, et al. Testosterone therapy in diabetes and pre-diabetes. Andrology. 2023 Feb;11(2):204–214.
  • Grossmann M, Ng Tang Fui M, Cheung AS. Late-onset hypogonadism: metabolic impact. Andrology. 2020 Nov;8(6):1519–1529. doi: 10.1111/andr.12705
  • Mangolim AS, Brito LAR, Nunes-Nogueira VDS. Effectiveness of testosterone replacement in men with obesity: a systematic review and meta-analysis. Eur J Endocrinol. 2021 Dec 3;186(1):123–135. doi: 10.1530/EJE-21-0473
  • Chung MK, Eckhardt LL, Chen LY, et al. Lifestyle and risk factor modification for reduction of atrial fibrillation: a scientific statement from the American Heart Association. Circulation. 2020 Apr 21;141(16):e750–e772. doi: 10.1161/CIR.0000000000000748
  • Schnabel RB, Yin X, Gona P, et al. 50 year trends in atrial fibrillation prevalence, incidence, risk factors, and mortality in the Framingham heart study: a cohort study. Lancet. 2015 Jul 11;386(9989):154–162. doi: 10.1016/S0140-6736(14)61774-8
  • Salem JE, Waintraub X, Courtillot C, et al. Hypogonadism as a reversible cause of torsades de pointes in men. Circulation. 2018 Jul 3;138(1):110–113. doi: 10.1161/CIRCULATIONAHA.118.034282
  • Banga S, Mishra M, Heinze-Milne SD, et al. Chronic testosterone deficiency increases late inward sodium current and promotes triggered activity in ventricular myocytes from aging male mice. Am J Physiol Heart Circ Physiol. 2023 Aug 1;325(2):H264–h277. doi: 10.1152/ajpheart.00505.2022
  • Gutierrez G, Wamboldt R, Baranchuk A. The impact of testosterone on the qt interval: a systematic review. Curr Probl Cardiol. 2022 Sep;47(9):100882. doi: 10.1016/j.cpcardiol.2021.100882
  • Kim J, Freeman K, Ayala A, et al. Cardiovascular impact of androgen deprivation therapy: from basic biology to clinical practice. Curr Oncol Rep. 2023 Sep;25(9):965–977.
  • Corona G, Filippi S, Bianchi N, et al. Cardiovascular risks of androgen deprivation therapy for prostate cancer. World J Mens Health. 2021 Jul;39(3):429–443.
  • Kurokawa J, Kodama M, Clancy CE, et al. Sex hormonal regulation of cardiac ion channels in drug-induced QT syndromes. Pharmacol Ther. 2016 Dec;168:23–28. doi: 10.1016/j.pharmthera.2016.09.004
  • Muensterman ET, Jaynes HA, Sowinski KM, et al. Effect of transdermal testosterone and oral progesterone on drug-induced QT interval lengthening in older men: a randomized, double-blind, placebo-controlled crossover-design study. Circulation. 2019 Sep 24;140(13):1127–1129. doi: 10.1161/CIRCULATIONAHA.119.041395
  • Tomaselli Muensterman E, Jaynes HA, Sowinski KM, et al. Transdermal testosterone attenuates drug-induced lengthening of both early and late ventricular repolarization in older men. Clin Pharmacol Ther. 2021 Jun;109(6):1499–1504.
  • Pizzocaro A, Vena W, Condorelli R, et al. Testosterone treatment in male patients with Klinefelter syndrome: a systematic review and meta-analysis. J Endocrinol Invest. 2020 Dec;43(12):1675–1687.
  • Isidori AM, Aversa A, Calogero A, et al. Adult- and late-onset male hypogonadism: the clinical practice guidelines of the Italian Society of Andrology and Sexual Medicine (SIAMS) and the Italian Society of Endocrinology (SIE). J Endocrinol Invest. 2022 Dec;45(12):2385–2403.
  • Salonia A, Bettocchi C, Boeri L, et al. European association of urology guidelines on sexual and reproductive health-2021 update: male sexual dysfunction. Eur Urol. 2021 Sep;80(3):333–357.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.