Late‐onset hypogonadism: Reductio ad absurdum of the cardiovascular risk‐benefit of testosterone replacement therapy

Abstract

Background Low testosterone (T) level is considered a marker of poor cardiovascular health. Ten years ago, the Testosterone in Older Men with Mobility Limitations (TOM) trial was discontinued due to a higher number of adverse events in men receiving T compared with placebo. Since then, several studies have investigated the risks of T replacement therapy (TRT) in late‐onset hypogonadism (LOH). Objective To review the mechanism by which TRT could damage the cardiovascular system. Materials and methods Comprehensive literature search of recent clinical and experimental studies. Results The mechanisms of T‐mediated coronary vasodilation were reviewed with emphasis on calcium‐activated and ATP‐sensitive potassium ion channels. We showed how T regulates endothelial nitric oxide synthase (eNOS) and phosphoinositide 3‐kinase/protein kinase B/eNOS signaling pathways in vessel walls and its direct effects on cardiomyocytes via β1‐adrenergic and ryanodine receptors and provided data on myocardial infarction and heart failure. Vascular smooth muscle senescence could be explained by the modulation of growth factors, matrix metalloproteinase‐2, and angiotensin II by T. Furthermore, leukocyte trafficking, facilitated by changes in TNF‐α, could explain some of the effects of T on atheromatous plaques. Conflicting data on prothrombotic risk linked to platelet aggregation inhibition via NO‐triggered arachidonate synthesis or increased aggregability due to enhanced thromboxane A in human platelets provide evidence regarding the hypotheses on plaque maturation and rupture risk. The effects of T on cardiac electrophysiology and oxygen delivery were also reviewed. Discussion The effects of TRT on the cardiovascular system are complex. Although molecular studies suggest a potential benefit, several clinical observations reveal neutral or occasionally detrimental effects, mostly due to confounding factors. Conclusions Attempts to demonstrate that TRT damages the cardiovascular system via systematic analysis of the putative mechanisms led to the contradiction of the initial hypothesis. Current evidence indicates that TRT is safe once other comorbidities are addressed.

Late‐onset hypogonadism a challenging task for the andrology field

“…Conversely, the role of TRT in improving other LOH‐related symptoms such as mobility and cognition impairment, as well as mood disturbances, is more conflicting 7,8 . Similarly, despite the fact that reduced T levels have been associated with worse metabolic profiles as well as with a higher cardiovascular (CV) risk, the current data only partially support the use of TRT for improving the latter conditions 9,13 . Finally, while TRT can contribute to the improvement of bone mineral density in osteoporotic subjects, its specific role in preventing bone fracture is unknown 10 …”

“…The 10th European Congress of Andrology (ECA), held in Budapest (11)(12)(13) October 2018), was a great success, including up to 500 participants from 50 different countries. One of the most attended sessions was the one dealing with different controversial aspects of late-onset hypogonadism (LOH).…”

“…7,8 Similarly, despite the fact that reduced T levels have been associated with worse metabolic profiles as well as with a higher cardiovascular (CV) risk, the current data only partially support the use of TRT for improving the latter conditions. 9,13 Finally, while TRT can contribute to the improvement of bone mineral density in osteoporotic subjects, its specific role in preventing bone fracture is unknown . 10 Prostate safety has been considered among the most risky side effects related to TRT.…”

“…14 The CV safety of TRT represents another conflicting aspect of LOH. Available data summarized in a specific paper included in this special issue 13 jsp?curl=pages/ medic ines/human/ refer rals/Testo stero necon taini ng_medic ines/human_refer ral_prac_000037.jsp&mid=WC0b0 1ac05 805c516f.). The different pattern of T prescriptions between the US and Europe, reported above, can explain, at least partially, these two apparently opposite positions.…”

“…However, it is | 1505 EDITORIAL important to recognize that long-term CV safety of TRT in LOH has still not been completely clarified and more long-term RCTs should be performed. 13 In line with this aim, a multi-center RCT is underway to specifically investigate the CV risk of TRT (clinicaltrials.gov: NCT03518034).…”