Effectiveness of T therapy in hypogonadal patients and its controversial adverse impact on the cardiovascular system

[madman]

Effectiveness of testosterone therapy in hypogonadal patients and its controversial adverse impact on the cardiovascular system


ABSTRACT

Testosterone is the major male hormone produced by testicles that are directly associated with man’s appearance and secondary sexual developments. Androgen deficiency starts when the male hormonal level falls from its normal range though, in youngsters, the deficiency occurs due to disruption of the normal functioning of pituitary, hypothalamus glands, and testes. Thus, testosterone replacement therapy was already known for the treatment of androgen deficiency with lesser risks of producing cardiovascular problems. Since from previous years, the treatment threshold in the form of testosterone replacement therapy has effectively increased to that extent that it was prescribed for those conditions which it was considered inappropriate. However, there are some research studies and clinical trials available that proposed a higher risk of inducing cardiovascular disease with the use of testosterone replacement therapy. Thus under the light of these results, the FDA has published the report of the increased risk of cardiovascular disease with the increased use of testosterone replacement therapy. Nevertheless, there is not a single trial available or designed that could evaluate the risk of cardiovascular events with the use of testosterone replacement therapy. As a result, the use of testosterone still questioned the cardiovascular safety of this replacement therapy. Thus, this literature outlines the distribution pattern of disease by investigating the data and link between serum testosterone level and the cardiovascular disease, also the prescription data of testosterone replacement therapy patients and their tendency of inducing cardiovascular disease, meta-analysis and the trials regarding testosterone replacement therapy and its connection with the risks of causing cardiovascular disease and lastly, the possible effects of testosterone replacement therapy on the cardiovascular system. This study aims to evaluate the available evidence regarding the use of testosterone replacement therapy when choosing it as a treatment plan for their patients




Effect of endogenous testosterone on the cardiovascular events – The TRNASVERSE trial

TRAVERSE trial (US National Library of Medicine) is known as the first randomized controlled trial that is used to analyze the cardiovascular events that occurred due to testosterone replacement therapy. Thus, to start these trials in 2018 researchers plan a scheme with 6000 men ranging between 45 and 80 years of age who were at risk of cardiovascular disease were treated with testosterone <300 ng/dl in gel form or treated with placebo. The treatment period selected for this plan was 5 years and the foremost endpoint selected for this study was MACE (nonfatal MI, nonfatal stroke, or death from cardiovascular causes). The other secondary results are achieved from the occurrence of the cardiovascular endpoint. The findings associated with these trials provide the documented results of cardiovascular safety by the use of testosterone replacement therapy.




Conclusions

T plays an important role in regulating body functions which include the cardiovascular system and metabolic system of the body. However, the population study contradicts the collected data and the clinical trials conducted yet. There are many studies still present that corroborate the facts about mortality due to testosterone replacement therapy. While several other studies in randomized trials documented the increased severity of cardiovascular risks due to testosterone therapy. Some contradictions were also seen in meta-analyses and were constrained in the range of low to medium trials. In addition, till now there is no authentic publication or research available that has the capability to evaluate its effect on cardiovascular risks associated with T. Thus for this purpose, a TRAVERSE trial (US National Library of Medicine) uses long-term treatment and the conclusions for the evaluation of cardiovascular events produced due to testosterone therapy. Thus, it is necessary to make patients aware of the cardiovascular events induced by testosterone replacement therapy.

 

[madman]

Table 1. Studies to claim a direct correlation between endogenous androgen levels and cardiovascular risk.

 

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Table 2. Investigations claiming an indirect (androgen deprivation therapy in prostate cancer patients) correlation between endogenous androgen levels and cardiovascular risk.

 

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Table 3. Studies to claim no association between cardiovascular diseases and endogenous testosterone levels in elderly men.

 

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Table 4. Meta-analyses on the association between cardiovascular risk and TRT.

 

[madman]

Figure 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 various pre-clinical and clinical studies, testosterone has shown significant vasorelaxant, anti-atherosclerotic, anti-hyperlipidemic, and anti-inflammatory actions. Testosterone therapy has exerted fluid retention, positive inotropic influence on heart, T-wave prolongation, and reduction in QT interval in electrocardiograph. nNOS: neuronal nitric oxide synthase; TNF-a: tumor 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.