European Journal of Cardiovascular Medicine

Male hypogonadism is characterized by impaired testicular function resulting in reduced testosterone production, abnormal spermatogenesis, or both. A total serum testosterone level below 300 ng/dL is commonly used to define biochemical testosterone deficiency (1). The condition may arise from dysfunction at the testicular level termed primary hypogonadism or from impairment of the hypothalamic–pituitary axis causing secondary hypogonadism (2). Both congenital causes, such as Klinefelter’s syndrome and cryptorchidism, and acquired causes including chronic systemic illness, obesity, testicular damage, and endocrine disorders, contribute to its development (3).

A strong association exists between hypogonadism, obesity, metabolic syndrome, and Type 2 Diabetes Mellitus (T2DM). Obesity has reached epidemic levels worldwide and is characterized by excessive visceral adiposity that increases aromatase activity, leading to the conversion of testosterone to estradiol and suppression of the hypothalamic–pituitary–gonadal axis (4). This mechanism lowers circulating testosterone levels and promotes the “hypogonadal–obesity cycle,” characterized by increased fat mass, reduced muscle mass, and insulin resistance (5). Studies demonstrate that testosterone deficiency is present in up to 40% of men with T2DM, indicating a significant metabolic–endocrine interplay (6).

Men with coexisting hypogonadism and T2DM or obesity also exhibit higher risks of cardiovascular (CV) morbidity and mortality. Low testosterone levels are linked to endothelial dysfunction, dyslipidemia, systemic inflammation, and insulin resistance, all of which contribute to adverse cardiometabolic outcomes (7). Epidemiological data from population based cohorts indicate that testosterone deficiency may increase the risk of cardiovascular events by nearly 50%, emphasizing the importance of recognising hypogonadism as a cardiometabolic risk factor (8). Inflammatory mediators, including tumor necrosis factor alpha and interleukin 1 beta, further suppress gonadotropin secretion and worsen metabolic dysfunction in men with T2DM (9).

Globally, the prevalence of hypogonadism ranges from 10% to 40%, with higher rates reported in older adults and individuals with obesity and diabetes (10). In the Gulf region, population-based studies from Saudi Arabia and Jordan estimate testosterone deficiency rates between 8% and 24%, paralleling the region’s high burden of obesity and T2DM (11). The rising incidence of metabolic disorders underscores the increasing relevance of hypogonadism as a public health challenge. Effective diagnosis using testosterone assays, gonadotropin profiling, and clinical evaluation, followed by evidence-based management such as testosterone replacement therapy (TRT), remains essential in improving metabolic, sexual, and overall health outcomes in affected men (12).

Given the high prevalence of hypogonadism in men with obesity and T2DM, and the uncertainty regarding TRT’s cardiovascular safety, a systematic review is warranted to synthesize available evidence. This review evaluates the role of TRT in hypogonadal men with obesity and/or T2DM, with a specific focus on cardiovascular outcomes

Study Design: This study was designed as a systematic review to evaluate the effects of testosterone replacement therapy (TRT) on cardiovascular outcomes in hypogonadal men with type 2 diabetes mellitus (T2DM) and/or obesity. The methodology followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta Analyses) guidelines.

Search Strategy: A comprehensive literature search was conducted up to 15 August 2021 in the following databases:

• PubMed
• Web of Science
• Cochrane Library
• Google Scholar

The search used combinations of the following keywords and MeSH terms:

• “Male hypogonadism”
• “Testosterone” OR “testosterone replacement therapy” OR “androgen replacement therapy”
• “Type 2 diabetes mellitus” OR “diabetes”
• “Obesity” OR “metabolic syndrome”
• “Cardiovascular disease” OR “cardiovascular events”

Boolean operators (AND/OR) were applied to combine terms. Reference lists of relevant reviews and included studies were also screened manually to identify additional articles.

Inclusion criteria

Studies were eligible if they met the following conditions:

1. Study population included men with T2DM, obesity, or metabolic syndrome.
2. Participants were diagnosed with hypogonadism (total serum testosterone <300 ng/dL, or defined per study criteria).
3. Intervention included testosterone replacement therapy in any formulation (intramuscular, transdermal, oral, gel, undecanoate).
4. Reported cardiovascular outcomes (major adverse cardiovascular events, CV mortality, metabolic markers linked to CV risk).
5. Study designs: randomized controlled trials (RCTs), cohort studies, case–control studies, and large registry/observational studies.

Exclusion criteria

1. Participants receiving systemic glucocorticoid therapy within 3 months prior to study.
2. History of prostate cancer or elevated prostate specific antigen (PSA).
3. Studies without cardiovascular or metabolic endpoints.
4. Case reports, editorials, conference abstracts without full text.

Study Selection Process

• All identified studies (n=320) were imported into a reference manager.
• Duplicates were removed.
• Two reviewers independently screened titles and abstracts.
• Full texts were then assessed against eligibility criteria.
• Disagreements were resolved by consensus.

Figure. 1: Consort diagram of systematic review process

Data Extraction

Data were extracted independently by two reviewers into a structured form, including:

• Author and year of publication
• Study design and duration
• Number of participants, mean age
• Intervention type and dose of TRT
• Comparison group (placebo or untreated)
• Cardiovascular endpoints (CV events, CV mortality, metabolic outcomes)
• Main study findings

For RCTs, effect estimates and reported adverse events were recorded. For observational studies, relative risk, hazard ratios, and long term trends were noted.

Quality Assessment

• Randomized controlled trials (RCTs): Assessed using the Cochrane Risk of Bias Tool. Domains included randomization, allocation concealment, blinding, incomplete outcome data, and selective reporting.
• Observational studies: Evaluated using the Newcastle–Ottawa Scale (NOS), covering selection, comparability, and outcome assessment.
• Discrepancies in scoring were resolved by discussion among reviewers.

Data Synthesis

• Studies were stratified into observational and randomized controlled trial (RCT) categories.
• Due to heterogeneity in study design, TRT formulation, and outcome reporting, a narrative synthesis was performed.
• Where possible, outcomes were grouped under beneficial effects, neutral effects, and adverse cardiovascular outcomes.
• Recent meta analyses (last 20 years) were also reviewed to contextualize findings.

Study Selection

• Top of Form
• Bottom of Form

In this review, initially a total of 320 articles related to TRT in hypogonadal men have been identified. However, only 198 studies were eligible for the review (including 86 RCTs and 112 non RCTs). 75 RCTs and 97 non RCT were excluded as these RCTs and non RCTs did not come under the purview of inclusion criteria. Benefits of TRT and a reduced adverse cardiovascular event in TRT were observed in some of the RCTs. These RCTs were reviewed. A few RCTs showed a neutral effect on cardiovascular events. In non RCTs, 15 studies observed benefits of TRTs and some of the supported TRT as there is a reduced adverse cardiovascular event in TRT.

Table 1: The main highlights of the observational studies included in this review are as follows:

Table 2: Characteristics of RCTs included in this systematic review are as follows:

Table 1 and Table 2 show the selected 16 RCTs and 15 non RCTs respectively. After reviewing the full text of 31 studies, observational studies and Randomised controlled trials (RCTs) were analyzed. Last 20 years meta analyses were also reviewed. Selected RCTs included 2605 participants and Observational studies included 1836513 participants.

A total of 320 studies examining testosterone replacement therapy (TRT) in hypogonadal men were initially identified. After screening titles, abstracts, and full texts, 198 studies met the inclusion criteria, of which 86 were randomized controlled trials (RCTs) and 112 were observational studies. A total of 75 RCTs and 97 non RCTs were excluded because they did not fulfil the criteria of hypogonadal male populations, did not report cardiometabolic or cardiovascular outcomes, or lacked adequate comparator groups. Thus, 31 studies (16 RCTs and 15 observational studies) were included for final synthesis.

Across observational cohorts, TRT was associated with notable cardiometabolic improvements. Studies such as Anderson et al. (13), Haider et al. (15), Muraleedharan et al. (17), Shores et al. (18), Reddy et al. (19), and Saad et al. (21) demonstrated beneficial effects on survival, waist circumference, obesity parameters, glycaemic control, and inflammatory markers. Long term registry studies, including those by Yassin et al. (24,25), further supported durable improvements in blood pressure, lipid profile, and metabolic syndrome components, with no increase in major cardiovascular (CV) events. A few observational studies, such as Maggi et al. (16) and Vigen et al. (26), showed increased CV risk among older and high risk patients; however, these findings were affected by methodological limitations and were inconsistent with the majority of evidence.

The 16 RCTs included 2,605 participants and predominantly reported neutral or favourable metabolic and cardiovascular outcomes. RCTs such as Aversa et al. (29,30), Francomano et al. (32), Giltay et al. (33), Groti et al. (34), Hackett et al. (35–37), Ho et al. (38), Jones et al. (39), Khripun et al. (40), Shigehara et al. (41), Stanworth et al. (42), and Shaikh et al. (43) consistently demonstrated improvements in insulin resistance, body composition, lipid parameters, sexual function, endothelial markers, and quality of life. The Cardiovascular Testosterone Trial (28) reported reduced non calcified plaque progression, although its clinical significance remains debated. Importantly, none of the included RCTs showed a statistically significant increase in major adverse cardiovascular events (MACE).

Across all studies, TRT consistently restored physiological testosterone concentrations regardless of dose form (intramuscular TU, transdermal gel, patch, or oral formulations). Overall, findings from both RCTs and observational data collectively suggest that TRT exerts beneficial effects on metabolic health while demonstrating a neutral to beneficial cardiovascular safety profile

This systematic review synthesizes evidence from RCTs, observational studies, and major meta analyses to evaluate the efficacy and cardiovascular safety of TRT in hypogonadal men, particularly those with type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS). Overall, the findings strongly suggest that TRT improves metabolic health, body composition, sexual function, and survival outcomes, and does not increase cardiovascular risk when appropriately monitored.

Observational studies provide robust real world evidence that TRT is associated with reduced mortality and improved cardiometabolic outcomes. The large health system study by Anderson et al. (13) showed that normalization of testosterone levels was not linked to increased CV events. Similarly, long term studies by Haider (15), Muraleedharan (17), Shores (18), Reddy (19), Salman (20), and Saad (21) consistently reported improvements in waist circumference, body weight, insulin sensitivity, lipid profiles, inflammatory markers, and overall survival. Some studies indicated increased CV risk, including Maggi et al. (16) and Vigen et al. (26); however, these have faced significant criticism related to methodological flaws, misclassification, residual confounding, and improper follow up adjustments. When viewed together, the overall balance of evidence leans strongly towards cardiometabolic benefit rather than harm.

In RCTs, which offer the highest level of evidence, TRT showed predominantly favourable metabolic and symptomatic outcomes. Trials conducted in men with T2DM or metabolic syndrome—including those by Aversa (29,30), Bayram (31), Giltay (33), Groti (34), Hackett (35–37), Ho (38), Jones (39), Khripun (40), Shigehara (41), and Stanworth (42)demonstrated improvements in insulin resistance, HbA1c, lipid profiles, endothelial function, depressive symptoms, sexual health, and quality of life. Importantly, none of the RCTs showed an excess of MACE, supporting the cardiovascular neutrality of TRT in controlled settings. Although the Testosterone Trials CV arm (28) reported reduced plaque progression, longer term implications remain unclear. Nevertheless, consistent symptomatic and metabolic benefits were observed, with favourable body composition changes seen across multiple RCTs (32,33,39).

Meta analyses further reinforce these findings. Systematic reviews by Corona et al. (101,102), Ponce et al. (103), and other pooled analyses demonstrate no significant increase in myocardial infarction, stroke, or CV mortality among TRT users. Meta analytic data also demonstrate improvements in waist circumference, fasting glucose, insulin resistance, lipid profiles, and lean body mass. These findings align well with the RCT evidence and contradict earlier concerns derived mainly from flawed analyses. Collectively, the data support that TRT is safe when prescribed with proper patient selection and monitoring.

Taken together, the results of this review indicate that TRT offers consistent and clinically meaningful improvements in metabolic and symptomatic outcomes with no evidence of excess cardiovascular risk. The convergence of high quality RCTs, real world registry data, and multiple meta analyses supports the use of TRT as a therapeutic option for men with clinically confirmed hypogonadism particularly those with obesity, T2DM, and metabolic syndrome provided that treatment is individualized and carefully monitored.

TRT in hypogonadal men with T2DM and obesity is associated with consistent improvements in metabolic and symptomatic outcomes, including insulin sensitivity, visceral adiposity, and sexual function. While observational studies suggest conflicting cardiovascular effects, RCT evidence largely indicates neutral to beneficial outcomes, with no definitive signal of increased CV risk. Current evidence supports the cautious use of TRT in selected hypogonadal men with obesity and/or T2DM, accompanied by comprehensive risk assessment and ongoing monitoring. Larger and longer term RCTs are urgently needed to establish the cardiovascular safety profile of TRT in this high risk population.

1. Corona G, Rastrelli G, Maggi M. Diagnosis and treatment of late onset hypogonadism: systematic review and meta analysis of testosterone replacement therapy outcomes. Best Pract Res Clin Endocrinol Metab. 2013 Aug;27(4):557–79.
2. Basaria S. Male hypogonadism. Lancet. 2014 Apr 5;383(9924):1250–63.
3. Pivonello R, Menafra D, Riccio E, Garifalos F, Mazzella M, De Angelis C, Colao A. Metabolic disorders and male hypogonadotropic hypogonadism. Front Endocrinol (Lausanne). 2019 Jul 25;10:345.
4. World Health Organization. Global Recommendations on Physical Activity for Health. Geneva: WHO Press; 2010. Available from: https://www.who.int/dietphysicalactivity/publications/9789241599979/en/
5. Ginter E, Simko V. Diabetes type 2 pandemic in 21st century. Bratisl Lek Listy. 2010;111(3):134–7.
6. Dhindsa S, Ghanim H, Batra M, Dandona P. Hypogonadotropic hypogonadism in men with diabesity. Diabetes Care. 2018 Jul;41(7):1516–25.
7. Corona G, Bianchini S, Sforza A, Vignozzi L, Maggi M. Hypogonadism as a possible link between metabolic diseases and erectile dysfunction in aging men. Hormones (Athens). 2015;14(4):569–78.
8. Anaissie J, DeLay KJ, Wang W, Hatzichristodoulou G, Hellstrom WJG. Testosterone deficiency in adults and corresponding treatment patterns across the globe. Transl Androl Urol. 2017 Apr;6(2):183–91.
9. Watanobe H, Hayakawa Y. Hypothalamic interleukin 1β and tumor necrosis factor α mediate endotoxin induced suppression of the reproductive axis in rats. Endocrinology. 2003 Nov;144(11):4868–75.
10. Fraietta R, Zylberstejn DS, Esteves SC. Hypogonadotropic hypogonadism revisited. Clinics (Sao Paulo). 2013 Jan;68(1):81–8.
11. ALNohair S. Obesity in gulf countries. Int J Health Sci (Qassim). 2014 Jan;8(1):79–83.
12. Snyder PJ, Matsumoto AM, Martin KA. Testosterone treatment of male hypogonadism. UpToDate. Waltham, MA: UpToDate Inc.; Updated September 30, 2009. Accessed January 3, 2010.
13. Anderson JL, May HT, Lappé DL, Bair TL, Le V, Carlquist JF, 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):794–801. doi:10.1016/j.amjcard.2015.11.063.
14. Yassin DJ, Doros G, Hammerer PG, Yassin AA. Long term testosterone treatment in elderly men with hypogonadism and erectile dysfunction reduces obesity parameters and improves metabolic syndrome and health related quality of life. J Sex Med. 2014 Jun;11(6):1567–76. doi:10.1111/jsm.12523.
15. Haider A, Yassin A, Haider KS, Doros G, Saad F, Rosano GM. Men with testosterone deficiency and a history of cardiovascular diseases benefit from long term testosterone therapy: observational, real life data. Vasc Health Risk Manag. 2016 Jun 14;12:251–61. doi:10.2147/VHRM.S108947.
16. Maggi M, Wu FC, Jones TH, Jackson G, Behre HM, Hackett G, et al. Testosterone treatment is not associated with increased risk of adverse cardiovascular events: results from RHYME registry. Int J Clin Pract. 2016;70(10):843–52. doi:10.1111/ijcp.12876.
17. 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 Dec;169(6):725–33. doi:10.1530/EJE 13 0321.
18. 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.
19. Reddy KC, Yadav SB. Effect of testosterone replacement therapy on insulin sensitivity and body composition in congenital hypogonadism: A prospective longitudinal follow up study. J Postgrad Med. 2021;67(2):67–74. doi:10.4103/jpgm.JPGM_887_20.
20. Salman M, Yassin DJ, Shoukfeh H, Nettleship JE, Yassin A. Early weight loss predicts long term obesity improvement in men with erectile dysfunction and hypogonadism receiving testosterone therapy. Aging Male. 2017;20(1):45–8. doi:10.1080/13685538.2016.1260107.
21. Saad F, Yassin A, Doros G, Haider A. Long term treatment with testosterone leads to weight loss and waist circumference reduction in 411 hypogonadal men. Int J Obes (Lond). 2016 Jan;40(1):162–70. doi:10.1038/ijo.2015.139.
22. Sonmez A, Haymana C, Bolu E, Aydogdu A, Tapan S, Serdar M, et al. Metabolic syndrome and the effect of testosterone treatment in young men with congenital hypogonadotropic hypogonadism. Eur J Endocrinol. 2011;164(5):759–64. doi:10.1530/EJE 10 0951.
23. Traish AM, Haider A, Doros G, Saad F. Long term testosterone therapy in hypogonadal men ameliorates metabolic syndrome components. Int J Clin Pract. 2014;68(3):314–29. doi:10.1111/ijcp.12319.
24. Yassin A, Almehmadi Y, Saad F, Doros G, Gooren L. Effects of intermission and resumption of testosterone therapy on metabolic parameters in hypogonadal men. Clin Endocrinol (Oxf). 2016;84(1):107–14. doi:10.1111/cen.12936.
25. Yassin AA, Nettleship J, Almehmadi Y, Salman M, Saad F. Continuous long term testosterone therapy in elderly hypogonadal men: 10 year data. Andrologia. 2016 Sep;48(7):793–9. doi:10.1111/and.12514.
26. Vigen R, O’Donnell CI, Baron AE, Grunwald GK, Maddox TM, Bradley SM, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke. JAMA. 2013 Nov;310(17):1829–36. doi:10.1001/jama.2013.280386.
27. Zhang LT, Shin YS, Kim JY, Park JK. Testosterone replacement therapy improves anemia and metabolic syndrome in hypogonadal men. J Urol. 2016 Apr;195(4):1057–64. doi:10.1016/j.juro.2015.10.130.
28. Abd Alamir M, Ellenberg SS, Swerdloff RS, Wenger NK, Mohler ER 3rd, Lewis CE, et al. The Cardiovascular Trial of the Testosterone Trials: Rationale, design, and baseline data. Coron Artery Dis. 2016;27(2):95–103. doi:10.1097/MCA.0000000000000321.
29. Aversa A, Bruzziches R, Francomano D, Rosano G, Spera G, Lenzi A. Effects of testosterone undecanoate on CV risk factors in metabolic syndrome. J Sex Med. 2010;7(10):3495–503. doi:10.1111/j.1743 6109.2010.01931.x.
30. Aversa A, Bruzziches R, Francomano D, Spera G, Lenzi A. Safety and efficacy of different testosterone formulations in metabolic syndrome. J Endocrinol Invest. 2010;33(11):776–83. doi:10.1007/BF03350341.
31. Bayram F, Elbuken G, Korkmaz C, Aydogdu A, Karaca Z, Cakir I. Effects of gonadotropin replacement on metabolic parameters in idiopathic hypogonadism. Horm Metab Res. 2016;48(2):112–7. doi:10.1055/s 0035 1564252.
32. Francomano D, Bruzziches R, Barbaro G, Lenzi A, Aversa A. Testosterone undecanoate plus diet improves body composition. J Endocrinol Invest. 2014;37(4):401–11. doi:10.1007/s40618 014 0066 9.
33. Giltay EJ, Tishova YA, et al. Testosterone supplementation improves depressive symptoms and metabolic parameters. J Sex Med. 2010;7(7):2572–82. doi:10.1111/j.1743 6109.2010.01859.x.
34. Groti K, Žuran I, Antonič B, Foršnarič L, Pfeifer M. Effect of testosterone replacement on vascular and glycemic outcomes in obese men with T2DM. Aging Male. 2018;21(3):158–69. doi:10.1080/13685538.2018.1468429.
35. Hackett G, Cole N, Mulay A, Strange RC, Ramachandran S. Long term TRT in T2DM: No increased CV events. BJU Int. 2019;123(3):519–29. doi:10.1111/bju.14536.
36. Hackett G, Cole N, Bhartia M, Kennedy D, Raju J, Wilkinson P. TRT and sexual desire in men with T2DM. Andrology. 2017;5(5):905–13. doi:10.1111/andr.12399.
37. Hackett G, Cole N, Mulay A, Strange RC, Ramachandran S. Long acting TRT improves QoL. J Sex Med. 2013;10(6):1612–27. doi:10.1111/jsm.12146.
38. Ho CC, Tong SF, Low WY, Ng CJ, Khoo EM, Lee VK, et al. TRT improves Aging Male Symptoms Scale outcomes. BJU Int. 2012;110(2):260–5. doi:10.1111/j.1464 410X.2011.10755.x.
39. Jones TH, Arver S, Behre HM, Buvat J, Meuleman E, Moncada I, et al. Testosterone replacement in hypogonadal men with T2DM/metabolic syndrome (TIMES2). Diabetes Care. 2011;34(4):828–37.
40. Khripun I, Vorobyev S, et al. Testosterone improves carbohydrate metabolism in T2DM. Aging Male. 2019;22(4):241–9. doi:10.1080/13685538.2018.1506918.
41. Shigehara K, Konaka H, Kato Y, et al. One year TRT improves metabolic factors in hypogonadal men with T2DM. Int J Impot Res. 2019;31(1):25–30. doi:10.1038/s41443 018 0065 z.
42. Stanworth RD, Akhtar S, et al. Effects of TRT on metabolic syndrome and insulin resistance. Eur J Endocrinol. 2013;170(2):193–200. doi:10.1530/EJE 13 0703.
43. Shaikh K, Ellenberg SS, et al. Testosterone gel vs placebo in older men with obesity and T2DM. J Clin Endocrinol Metab. 2020;105(7):2142–9. doi:10.1210/clinem/dgz242