Testosterone therapy in hypogonadal patients and the associated risks of cardiovascular events

[madman]

ABSTRACT

Since the male secondary sex characters, libido and fertility are attributed to their major androgen hormone testosterone, the sub-optimum levels of testosterone in young adults may cause infertility and irregularities in their sexual behaviour. Such deficiency is often secondary to maladies involving testes, pituitary or hypothalamus that could be treated with an administration of exogenous testosterone. In the last few decades, the number of testosterone prescriptions has markedly increased to treat sub-optimal serum levels even though its administration in such conditions is not yet approved. On account of its associated cardiovascular hazards, the food and drug authority in the United States has issued safety alerts on testosterone replacement therapy (TRT). Owing to a great degree of conflict among their findings, the published clinical trials seem struggling in presenting a decisive opinion on the matter. Hence, the clinicians remain uncertain about the possible cardiovascular adversities while prescribing TRT in hypogonadal men. The uncertainty escalates even further while prescribing such therapy in older men with a previous history of cardiovascular ailments. In the current review, we analysed the pre-clinical and clinical studies to evaluate the physiological impact of testosterone on cardiovascular and related parameters. We have enlisted studies on the association of cardiovascular health and endogenous testosterone levels with a comprehensive analysis of epidemiological studies, clinical trials, and meta-analyses on the cardiovascular risk of TRT. The review is aimed to assist clinicians in making smart decisions regarding TRT in their patients.








7. Conclusions

Besides its primary role in male secondary sex character, fertility, and sexual behaviour, testosterone plays a significant regulatory role in metabolism, growth and cardiovascular functions. Testosterone deficiency may result in Hypogonadism and other serious health disorders in the elderly as well as young men. Over the past few decades, the number of testosterone prescriptions has been alarmingly increased around the globe to treat hypogonadism. Thus far, the available reports including epidemiological studies, clinical trials and meta-analyses have generated conflicting opinions in establishing an association between cardiovascular adversities and TRT. According to some retrospective assessments, TRT exerts advantageous effects on mortality. Other studies including some randomized trials, have associated the likeliness of severe cardiovascular risks with TRT. Succinctly, the imperative shortcomings in the study design, selection criteria and result analyses of most of such clinical trials and epidemiological studies may account for such conflicting findings. Besides, none of the published documents on TRT trials have been sufficiently powered to evaluate cardiovascular issues. Consequently, the TRAVERSE trial was initiated in 2018 to evaluate the cardiovascular risks/safety of TRT. The study is designed for five years to get a better understanding of this context. Meanwhile, to make smart decisions, clinicians should openly discuss with their patients about the prevailing data on the cardiovascular risks of TRT.

 

[madman]

Fig. 1. Physiological effects of testosterone on different organs and tissues. Testosterone is released from testis and to some extent from the adrenal medulla. Based on several pre-clinical and clinical studies, testosterone has exhibited considerable vasorelaxant, anti-atherosclerotic, anti-hyperlipidemic and anti-inflammatory effect. Testosterone treatment has shown fluid retention, +ve inotropic effect on heart, T-wave prolongation and shortening of QT interval in electrocardiograph. Abbreviations: nNOS: neuronal nitric oxide synthase; TNF-α: tumour necrosis factor-alpha; IL: interleukin; VCAM1: vascular cell adhesion molecule-1; ICAM-1: intercellular adhesion molecule-1; SCARB1: scavenger receptor class B type 1; LDL: low-density lipoprotein.

 

[madman]

Effects of Long-term Testosterone Treatment on Cardiovascular Outcomes in Men with Hypogonadism

ABSTRACT Background: Testosterone exerts some effects on the cardiovascular system that could be considered beneficial; some other effects may potentially increase the risk of cardiovascular (CV) events. Neither the long-term efficacy nor safety of testosterone treatment has been studied in an...

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[madman]

Innovations in Testosterone Therapy in Men Treated for Prostate Cancer

Urology Times® is celebrating its 50th anniversary in 2022. To mark the occasion, we are highlighting 50 of the top innovations and developments that have transformed the field of urology over the past 50 years. In this installment, Amy Pearlman, MD, interviews Mohit Khera, MD, MBA, MPH on how...

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[madman]

Testosterone Therapy and the Risk of Cardiovascular Disease

Abstract The debate over the cardiovascular (CV) implications of testosterone therapy (TT) have resulted in diverging safety recommendations and clinical guidelines worldwide. This narrative review synthesizes and critically evaluates long-term studies examining the effects of TT within the...

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4. Conclusion

The therapeutic approach for TT for symptomatic hypogonadism and low testosterone levels associated with aging, obesity, and systemic illness presents challenges. These conditions are intricately linked with CVD outcomes and may confound the relationship between low testosterone and CVD. Although observational studies suggest an association between low testosterone and increased risk of CVD, results from testosterone supplementation are inconsistent. RCTs indicate that short-term TT at standard replacement is not associated with increased CVD risk. Nevertheless, the cardiovascular sub-study of T Trials observed increases in NCP and CAC, signaling the need for further investigation into potential long-term implications of TT.

The TRAVERSE trial, a landmark study unique in its capacity to evaluate CVD events, contributes valuable insights into the short-term safety of TT at lower physiological levels. However, the long-term effects and implications of mid to high physiological testosterone levels are not yet fully understood. The trials’ limitations — achievement of only low-normal testosterone levels, high discontinuation rates, brief follow-up period, and high loss to follow-up rate — suggest that the findings should be interpreted with caution. It is important to avoid generalizing the safety of TT based on these results alone and to approach the extrapolation of TRAVERSE’s conclusions to higher dosages or longer-term therapy with caution.

The decision to initiate TT requires a nuanced approach, which must account for current gaps in evidence regarding CV safety. A personalized assessment and management of CVD risk factors is essential for older men with known CVD. The CV effects of exogenous testosterone, when given to maintain physiological levels, remain to be fully explored. In this regard, an important question remains the identification of male patients with symptomatic hypogonadism who may benefit from TT. This topic continues to be the subject of ongoing debate. Hopefully, future trials will provide clarity on whether TT confers beneficial, neutral, or adverse cardiovascular effects in middle-aged and older men. Until definitive evidence surfaces, clinical practice should exercise caution and prioritize individualized care with informed discussions regarding the potential CV implications of TT.