Testosterone tales:
Exploring the benefits and risks of TRT in ageing men 

Testosterone levels decrease by ~3.4nmol/l every 10 years, equating to an average annual decline of 1%-2% in men >30-years. This rate can be further influenced by factors such as body fat, medications, and chronic diseases.² 

 What is the impact of low testosterone on men's health? 
Beyond its essential role in the development and maintenance of male characteristics and sexual organs, testosterone impacts major organs including the brain, muscles, kidneys, bones, liver, and skin. Testosterone deficiency (TD) or hypogonadism, can lead to clinical consequences such as reduced libido and vitality, decreased mobility, lower energy levels, osteoporosis, and an increased risk of mortality.³ 

 Apart from ageing, TD is more prevalent in men with certain conditions, including obesity, diabetes, hypertension, hyperlipidaemia, asthma, chronic obstructive pulmonary disease, and prostatic disease.³  

Effects of TRT on cardiovascular health 

Conflicting evidence over decades regarding testosterone and major adverse cardiovascular events (MACE) has led to considerable uncertainty among clinicians and patients.⁴ 

As a result, the American Food and Drug Administration (FDA) issued a guidance in 2015, requiring manufacturers of approved testosterone products to conduct clinical trials to determine whether TRT is associated with an increased risk of CV events.⁴  

To provide definitive answers, the FDA commissioned the largest testosterone trial ever: A Study to Evaluate the Effect of Testosterone Replacement Therapy (TRT) on the Incidence of Major Adverse Cardiovascular Events (MACE) and Efficacy Measures in Hypogonadal Men (TRAVERSE).⁴ 

 The findings were published last year in the prestigious New England Journal of Medicine. TRAVERSE was a phase IV, randomised, double-blind, placebo-controlled, non-inferiority trial conducted across 316 clinical sites in the United States. The study enrolled 5246 participants. Exclusion criteria included congenital or acquired severe hypogonadism (<3.5nmol/l), a history of prostate cancer (PCa) or prostate nodules, an elevated screening prostate-specific antigen (PSA) level, thrombophilia, and uncontrolled heart failure.⁴  

Participants, aged 45- to 80-years, were randomised 1:1 to receive daily transdermal 1.62% testosterone gel (this formulation is not currently available in South Africa, only testosterone 1% gel is registered by South African Health Products Regulatory Authority) or placebo, with adjustments to maintain testosterone levels between 12nmol/l 25nmol/l. All participants had either established CVD or multiple CV risk factors. The primary safety endpoint was the occurrence of MACE, defined as CV death, non-fatal myocardial infarction, or non-fatal stroke.⁴  

Secondary endpoints included a composite of MACE plus coronary revascularisation, all-cause mortality, and various CV and non-CV outcomes.⁴ 

The trial revealed several key findings:⁴ 

• The incidence of primary safety endpoint events (MACE) was similar between the TRT (7%) and placebo (7.3%) groups, demonstrating non-inferiority. 
• Secondary CV endpoints, including the composite of MACE plus coronary revascularisation, did not significantly differ between groups. 
• Changes in systolic blood pressure and other safety parameters were monitored. The TRT group had higher rates of atrial fibrillation (3.5% vs 2.4%), acute kidney injury (2.3% vs 1.5%), and pulmonary embolism (0.9% vs 0.5%) compared to placebo. 

According to Lincoff et al, the findings of their study suggest that TRT is comparable to placebo in terms of MACE over an average 22-month follow-up period among middle-aged and older men with hypogonadism and either established CVD or multiple CV risk factors. Moreover, the overall incidence of adverse events (AEs) was minimal, underscoring the potential for TRT to be considered more confidently in clinical decision-making.⁴ 

To find out more, watch this short video presented by Prof Lincoff, lead author of the TRAVERSE study.

Key sub-studies of the TRAVERSE trial 
In addition to the study on the effects of TRT on CV risk, the TRAVERSE study provided insights of the potential benefits and risks of TRT, briefly highlighted below:^5-8 

Risk of PCa and other adverse prostate events 
This sub-study compared TRT with a placebo regarding the incidence of high-grade PCa (Gleason score ≥4 + 3), any PCa, acute urinary retention, invasive prostate procedures, and pharmacologic treatment for lower urinary tract symptoms in men with hypogonadism. Men with PSA concentrations >3ng/ml and high International Prostate Symptom Scores (IPSS) were excluded.⁵ 

Participants were randomised to receive either topical 1.62% testosterone gel or placebo. The primary endpoint was the incidence of high-grade PCa, with secondary endpoints including other prostate-related events. Follow-up was 21.7 months.⁵  

Over a mean of 33 months of follow-up (equating to 14,304 person-years), the incidence of high-grade prostate cancer did not differ significantly between treatment groups [n=5/2596 (0.19%) in the TTh group vs n=3/2602 (0.12%) in the placebo group. The incidences of any prostate cancer, acute urinary retention, invasive surgical procedures for BPH, prostate biopsy, and new pharmacologic treatment for LUTS also did not differ significantly between treatment groups. Change in IPSS did not differ between groups, indicating no significant difference in occurrence of LUTS.⁵  

PSA concentrations increased more in the TRT group up to month 12, but thereafter, no significant between-group difference in PSA levels was observed ⁵ 

The study’s findings will facilitate a more informed appraisal of the potential prostate risks of testosterone replacement therapy.⁵ 

TRT's efficacy in improving sexual activity 
The Sexual Function Study, nested within the larger TRAVERSE trial, aimed to determine TRT's efficacy in enhancing sexual activity, hypogonadal symptoms, libido, and erectile function in men with low libido.⁶ 

Among 5204 men aged 45- to 80-years with pre-existing CVD or elevated CV risk, 1161 with low libido were enrolled. They were randomised to receive either 1.62% testosterone gel or a placebo gel for the study duration. The primary endpoint was the change from baseline in sexual activity score, while secondary endpoints included hypogonadal symptoms, erectile function, and sexual desire.⁶ 

Results showed that TRT significantly improved sexual activity compared to placebo, with an estimated mean difference of 0.49 and 0.47 acts per day at six- and 12-months, respectively, and this effect was sustained at 24-months. Additionally, TRT improved hypogonadal symptoms, sexual function and sexual desire but not erectile function compared to placebo.⁶ The observed treatment effects were irrespective of age (≥65/<65 years), prior CVD (yes/no), baseline testosterone level (<8.7/≥8.7 nmol/L) or race (White/African American).⁶ 

Can TRT correct or prevent the development of anaemia in men with hypogonadism? 
 Anaemia is prevalent in middle-aged and older adults and is associated with impaired quality of life, fatigue, mobility limitation, falls, and increased risk of mortality. Currently, there is no approved therapy for unexplained anaemia that occurs during ageing.⁷ 

TD causes mild normocytic anaemia and nearly 15% of older men with hypogonadism experience anaemia. TRT increases haemoglobin. The TRAVERSE Anaemia  sub-analysis aimed to assess TRT's efficacy in correcting anaemia in hypogonadal men with anaemia and reducing the risk of developing anaemia in those without the condition .⁷ 

Participants were randomised to receive either 1.62% testosterone gel or placebo daily. The primary endpoint was the proportion of anaemic participants (haemoglobin <12.7g/dL) whose condition resolved (haemoglobin ≥12.7g/dL). Secondary endpoints included the incidence of anaemia in non-anaemic men.⁷ 

Results showed that TRT corrected anaemia in a significantly higher proportion of men compared to placebo at multiple time points: 41% vs 27.5% at six-months, 45% vs 33.9% at 12-months, and similar trends at 24, 36, and 48-months. Furthermore, among men without anaemia, fewer in the TRT group developed anaemia compared to the placebo group. Changes in haemoglobin levels were also linked an improvement in energy levels.⁷ 

The effect of testosterone on depressive symptoms  
Among 5204 participants, 2643 had significant depressive symptoms, but only 49 met criteria for late-life-onset, low-grade persistent depressive disorder (LG-PDD). In men with LG-PDD, TRT did not significantly differ from placebo in improving depressive symptoms, likely due to low statistical power. However, in men with significant depressive symptoms and overall participants, TRT led to modest yet significant improvements in mood and energy levels but had no notable effects on cognition or sleep quality.⁸  

Conclusion 
The main objective of the TRAVERSE trial was to determine the effects of testosterone replacement therapy on major adverse cardiac events among middle-aged and older men with hypogonadism who are at high CV risk. Key findings revealed that TRT did not increase the risk of MACE among middle-aged or older men with hypogonadism, who had a history of established CVD or who were at high risk for incident CV events, compared to placebo, demonstrating its safety in this regard.  

Furthermore, the sub-analysis has shown that TRT demonstrated promise in alleviating depressive symptoms, particularly mood and energy levels, significantly improved sexual activity, sexual function and hypogonadal symptoms; corrected anaemia in hypogonadal men with the condition and provided robust evidence on prostate safety.  

These findings contribute vital insights for clinical decision-making regarding TRT in middle-aged and older men with hypogonadism and enable a more informed evaluation of the potential benefits and risks in this population. 

References 

1. Barone B, Napolitano L, Abate M, et al. The Role of Testosterone in the Elderly: What Do We Know? Int J Mol Sci, 2022. 
2. Cohen J, Nassau DE, Patel P, Ramasamy R. Low Testosterone in Adolescents & Young Adults. Front Endocrinol (Lausanne), 2020. 
3. Grober ED. Testosterone deficiency and replacement: Myths and realities. Can Urol Assoc J, 2014. 
4. Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular Safety of Testosterone-Replacement Therapy. NEJM, 2023. 
5. Bhasin S, Travison TG, Pencina KM, et al. Prostate Safety Events During Testosterone Replacement Therapy in Men with Hypogonadism: A Randomized Clinical Trial. JAMA Netw Open, 2023. 
6. Pencina KM, Travison TG, Cunningham GR, et al. Effect of Testosterone Replacement Therapy on Sexual Function and Hypogonadal Symptoms in Men with Hypogonadism. J Clin Endocrinol Metab, 2024. 
7. Pencina KM, Travison TG, Artz AS, et al. Efficacy of Testosterone Replacement Therapy in Correcting Anemia in Men with Hypogonadism: A Randomized Clinical Trial. JAMA Netw Open, 2023.   
8. Snyder PJ, Bauer DC, Ellenberg SS, et al. Testosterone Treatment and Fractures in Men with Hypogonadism. N Engl J Med, 2024.