ASSESSING CARDIOVASCULAR SAFETY OF TESTOSTERONE REPLACEMENT THERAPY FOR MALE HYPOGONADISM: A SYSTEMATIC REVIEW AND META-ANALYSIS

##plugins.themes.bootstrap3.article.main##

##plugins.themes.bootstrap3.article.sidebar##

PDF
Published 2024-09-06
Manarul Iman Alfafa Rachman Irene Yasmina Vilado Ilham Satriawan Jawaharlal Akbar Lalchanzani Nova Auliyatul Faida Angeline Asti Shiela Permata Pradana Nurhadi Besut Daryanto

Abstract

Objective: This study aims to comprehensively assess TRT's cardiovascular safety in males with hypogonadism, providing valuable insights for treatment decisions. Material & Methods: Adhering to PRISMA guidelines, we registered our PROSPERO protocol and analyzed relevant English-language randomized clinical trials published from 2008 to 2023. Results: Among 1187 initial papers, 7 studies met inclusion criteria, with 6 in quantitative analysis and all 7 in qualitative assessment. Our findings indicate that TRT does not significantly increase the risk of cardiovascular events compared to placebo. Specifically, the analysis of major adverse cardiac events (MACE) yielded an OR of 0.90 (95% CI: 0.74, 1.10; I² = 26%; p = 0.25), while the evaluation of all cardiovascular adverse events revealed an OR of 1.37 (95% CI: 0.73, 2.55; I² = 75%; p = 0.001). Conclusion: This study offers reassurance for clinical decision-making by suggesting that TRT is not significantly associated with an elevated cardiovascular risk in hypogonadal men, addressing the ongoing debates on this issue. Keywords: Cardiovascular safety, hypogonadism, testosterone replacement therapy.


##plugins.themes.bootstrap3.article.details##

Keywords

cardiovascular safety, hypogonadism, testosterone replacement therapy

References

Ahmed T, Alattar M, Pantalone K, Haque R. Is Testosterone Replacement Safe in Men with Cardiovascular Disease? Cureus. Published online March 19, 2020.

Kharaba ZJ, Buabeid MA, Ibrahim NA, et al. Testosterone therapy in hypogonadal patients and the associated risks of cardiovascular events. Biomed Pharmacother. 2020; 129: 110423.

Salonia A, Rastrelli G, Hackett G, et al. Paediatric and adult-onset male hypogonadism. Nat Rev Dis Primer. 2019; 5(1): 38.

Lopez DS, Canfield S, Wang R. Testosterone replacement therapy and the heart: friend, foe or bystander? Transl Androl Urol. 2016; 5(6): 898-908.

Yeo S, Holl K, Peñaherrera N, Wissinger U, Anstee K, Wyn R. Burden of Male Hypogonadism and Major Comorbidities, and the Clinical, Economic, and Humanistic Benefits of Testosterone Therapy: A Narrative Review. Clin Outcomes Res. 2021; 13: 31-38.

Thirumalai A, Anawalt BD. Epidemiology of Male Hypogonadism. Endocrinol Metab Clin North Am. 2022; 51(1): 1-27.

Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal Effects of Aging on Serum Total and Free Testosterone Levels in Healthy Men. J Clin Endocrinol Metab. 2001; 86(2): 724-731.

Bhasin S, Pencina M, Jasuja GK, et al. Reference Ranges for Testosterone in Men Generated Using Liquid Chromatography Tandem Mass Spectrometry in a Community-Based Sample of Healthy Nonobese Young Men in the Framingham Heart Study and Applied to Three Geographically Distinct Cohorts. J Clin Endocrinol Metab. 2011; 96(8): 2430-2439.

Wu FCW, Tajar A, Beynon JM, et al. Identification of Late-Onset Hypogonadism in Middle-Aged and Elderly Men. N Engl J Med. 2010; 363(2): 123-135.

Tajar A, Huhtaniemi IT, O’Neill TW, et al. Characteristics of Androgen Deficiency in Late-Onset Hypogonadism: Results from the European Male Aging Study (EMAS). J Clin Endocrinol Metab. 2012; 97(5): 1508-1516.

Hwang K, Miner M. Controversies in testosterone replacement therapy: testosterone and cardiovascular disease. Asian J Androl. 2015; 17(2): 187.

Gagliano-Jucá T, Basaria S. Trials of testosterone replacement reporting cardiovascular adverse events. Asian J Androl. 2018; 20(2): 131.

Sellke N, Omil-Lima D, Sun HH, et al. Trends in testosterone prescription during the release of society guidelines. Int J Impot Res. Published online May 2, 2023.

Ory J, White JT, Moore J, Grantmyre J. Trends In Testosterone Therapy. Fertil Steril. 2020; 114(3): e363-e364.

Handelsman DJ. Global trends in testosterone prescribing, 2000–2011: expanding the spectrum of prescription drug misuse. Med J Aust. 2013; 199(8): 548-551.

Vigen R. Association of Testosterone Therapy With Mortality, Myocardial Infarction, and Stroke in Men With Low Testosterone Levels. JAMA. 2013; 310(17): 1829.

Finkle WD, Greenland S, Ridgeway GK, et al. Increased Risk of Non-Fatal Myocardial Infarction Following Testosterone Therapy Prescription in Men. Gong Y, ed. PLoS ONE. 2014; 9(1): e85805.

Etminan M, Skeldon SC, Goldenberg SL, Carleton B, Brophy JM. Testosterone Therapy and Risk of Myocardial Infarction: A Pharmacoepidemiologic Study. Pharmacother J Hum Pharmacol Drug Ther. 2015; 35(1): 72-78.

Martinez C, Suissa S, Rietbrock S, et al. Testosterone treatment and risk of venous thromboembolism: population based case-control study. BMJ. 2016: i5968.

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

Tan RS, Cook KR, Reilly WG. Myocardial Infarction and Stroke Risk in Young Healthy Men Treated with Injectable Testosterone. Int J Endocrinol. 2015; 2015: 1-8.

Sharma R, Oni OA, Gupta K, et al. Normalization of Testosterone Levels After Testosterone Replacement Therapy Is Associated With Decreased Incidence of Atrial Fibrillation. J Am Heart Assoc. 2017; 6(5): e004880.

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; 97(6): 2050-2058.

Li H, Benoit K, Wang W, Motsko S. Association between Use of Exogenous Testosterone Therapy and Risk of Venous Thrombotic Events among Exogenous Testosterone Treated and Untreated Men with Hypogonadism. J Urol. 2016; 195(4 Part 1): 1065-1072.

Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. J Clin Epidemiol. 2009; 62(10): 1006-1012.

Chien PF, Khan KS, Siassakos D. Registration of systematic reviews: PROSPERO: Editorial. BJOG Int J Obstet Gynaecol. 2012; 119(8): 903-905.

Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular Safety of Testosterone-Replacement Therapy. N Engl J Med. 2023; 389(2): 107-117.

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; 195(3): 699-705.

Konaka H, Sugimoto K, Orikasa H, et al. Effects of long-term androgen replacement therapy on the physical and mental statuses of aging males with late-onset hypogonadism: a multicenter randomized controlled trial in Japan (EARTH Study). Asian J Androl. 2016; 18(1): 25.

Basaria S, Coviello AD, Travison TG, et al. Adverse Events Associated with Testosterone Administration. N Engl J Med. 2010; 363(2): 109-122.

Emmelot-Vonk MH, Verhaar HJJ, 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; 299(1).

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; 95(2): 639-650.

Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of Testosterone Treatment in Older Men. N Engl J Med. 2016; 374(7): 611-624.

Morgentaler A, Feibus A, Baum N. Testosterone and cardiovascular disease – the controversy and the facts. Postgrad Med. 2015; 127(2): 159-165.

Togun A, Sankar A, Karaca-Mandic P. FDA safety warnings and trends in testosterone marketing to physicians. Am J Manag Care. 2022; 28(3): e78-e79.

Section
Articles
Copyright Information
Department of Urology, Faculty of Medicine/Airlangga University