Trials of testosterone replacement reporting cardiovascular adverse events

Gagliano‐Jucá, Thiago; Basaria, Shehzad

doi:10.4103/aja.aja_28_17

Cited by 10 publications

(6 citation statements)

References 89 publications

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“…Higher dose of testosterone (100 µg/kg) not only did not mitigate renal injury but also increased both IL-10 and TNF-α levels. A recent review shared our point of view [ 7 ]. They pointed out that the number of testosterone prescriptions in the United States has increased in recent years.…”

Section: Discussionmentioning

confidence: 98%

“…For example, several studies indicated that testosterone protects against atherosclerosis and cardiometabolic syndrome [ 3 , 4 , 5 ]. On the contrary, some studies hold the opposite view that testosterone and its derivatives exert toxic effects on the cardiovascular system [ 6 , 7 ]. Animal experiments confirmed the mixed side effects of testosterone.…”

Section: Introductionmentioning

confidence: 99%

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Testosterone aggravates cerebral vascular injury by reducing plasma HDL levels

Jin

Wang

et al. 2020

Open Life Sciences

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Testosterone is often used to improve the physiological function. But increased testosterone levels affect blood lipids and cause inflammation and oxidative stress, which are risk factors for vascular diseases. This study aimed at investigating the effects of testosterone on cerebral vascular injury using an established intracranial aneurysm (IA) model. Sixteen-week-old female C57Bl/6 mice were subcutaneously infused with testosterone propionate (TP; 5 mg/kg day) or plain soybean oil (controls) for 6 weeks. After 2 weeks of treatment, mice were given angiotensin II-elastase for another 4 weeks. The results showed that TP significantly increased cell apoptosis and reactive oxygen species production in cerebral artery, together with increases in plasma tumor necrosis factor-α (TNF-α) levels and in urinary 8-isoprostane levels. Plasma assays showed that 2 weeks after TP or soybean oil administration, the high-density lipoprotein (HDL) level was higher in the TP group than in controls. In vitro studies showed that testosterone increased TNF-α and monocyte chemotactic protein-1 mRNA and protein expression levels in RAW 264.7 macrophages. In summary, by reducing the HDL level, TP aggravates cerebral artery injury by increasing cell apoptosis, inflammation, and oxidative stress.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Testosterone aggravates cerebral vascular injury by reducing plasma HDL levels

Jin

Wang

et al. 2020

Open Life Sciences

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“…There is conflicting information regarding the role of the sex hormones in regulating cell death in cardiac tissue, and therefore, indicated a need for further research in this area ( Djouadi et al, 1998 ; Morris and Channer, 2012 ; Hsieh et al, 2015 ; Wang F. et al, 2015 ; Gagliano-Juca and Basaria, 2018 ; Jones and Kelly, 2018 ). Cell death pathways, including apoptosis, autophagy, necrosis, and pyroptosis, have been implicated in inducing cell death in CVD among various cell types within the heart including cardiomyocytes, endothelial cells, and monocytes/macrophages ( Subramanian and Shaha, 2007 ; Wang F. et al, 2010 ; Chen et al, 2014 ; Feng et al, 2017 ; Amgalan et al, 2020 ; Di Florio et al, 2020 ).…”

Section: Cell Deathmentioning

confidence: 99%

Sex Hormone Regulation of Proteins Modulating Mitochondrial Metabolism, Dynamics and Inter-Organellar Cross Talk in Cardiovascular Disease

Lynch

Boyett

Smith

et al. 2021

Front. Cell Dev. Biol.

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Cardiovascular disease (CVD) is the leading cause of death in the U.S. and worldwide. Sex-related disparities have been identified in the presentation and incidence rate of CVD. Mitochondrial dysfunction plays a role in both the etiology and pathology of CVD. Recent work has suggested that the sex hormones play a role in regulating mitochondrial dynamics, metabolism, and cross talk with other organelles. Specifically, the female sex hormone, estrogen, has both a direct and an indirect role in regulating mitochondrial biogenesis via PGC-1α, dynamics through Opa1, Mfn1, Mfn2, and Drp1, as well as metabolism and redox signaling through the antioxidant response element. Furthermore, data suggests that testosterone is cardioprotective in males and may regulate mitochondrial biogenesis through PGC-1α and dynamics via Mfn1 and Drp1. These cell-signaling hubs are essential in maintaining mitochondrial integrity and cell viability, ultimately impacting CVD survival. PGC-1α also plays a crucial role in inter-organellar cross talk between the mitochondria and other organelles such as the peroxisome. This inter-organellar signaling is an avenue for ameliorating rampant ROS produced by dysregulated mitochondria and for regulating intrinsic apoptosis by modulating intracellular Ca2+ levels through interactions with the endoplasmic reticulum. There is a need for future research on the regulatory role of the sex hormones, particularly testosterone, and their cardioprotective effects. This review hopes to highlight the regulatory role of sex hormones on mitochondrial signaling and their function in the underlying disparities between men and women in CVD.

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“… 4 As they note, some randomized controlled trials have reported increased cardiovascular events in older men with prevalent cardiovascular disease. 5 Although the United States Testosterone Trial, the largest placebo-controlled trial of testosterone therapy in older men to date, did not demonstrate increased cardiovascular events after one year of testosterone replacement therapy compared to placebo, there was an increased risk of progression of non-calcified coronary plaque. 6 7 …”

mentioning

confidence: 99%

Conclusions about testosterone therapy and cardiovascular risk

Anawalt

Yeap

2018

Asian J Androl

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In this issue of Asian Journal of Andrology (AJA), several experts have reviewed the latest data on the potential and known effects of endogenous and exogenous testosterone (T) on cardiovascular risk. In the review by Meyer and Wittert, low endogenous serum T appears to be associated with higher risk of cardiovascular disease and overall mortality in certain populations such as Klinefelter syndrome and older men, but not in men with congenital hypogonadotropic hypogonadism.1 Whether this association is causal or whether low serum testosterone is a marker of other risk factors for cardiovascular disease such as obesity, diabetes mellitus, or other systemic disease is unknown. In Yeap's review of the relationship between circulating endogenous testosterone and its major metabolites, dihydrotestosterone, and estradiol, he raises the provocative hypotheses that there might be differential effects on cardiovascular and cerebrovascular risk related to endogenous testosterone and dihydrotestosterone concentrations.2 Based on the same epidemiological studies, Yeap postulates that there might be a U-shaped curve for circulating endogenous androgen concentrations such that lower and higher concentrations might confer greater risk of cardiovascular events and all-cause mortality than midrange concentrations. Shores demonstrates in a carefully done review of studies of large prescription databases (including >200 000 men) that testosterone therapy is not associated with overall mortality, myocardial infarction, stroke, or deep venous thrombosis events.3

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Trials of testosterone replacement reporting cardiovascular adverse events

Cited by 10 publications

References 89 publications

Testosterone aggravates cerebral vascular injury by reducing plasma HDL levels

Testosterone aggravates cerebral vascular injury by reducing plasma HDL levels

Sex Hormone Regulation of Proteins Modulating Mitochondrial Metabolism, Dynamics and Inter-Organellar Cross Talk in Cardiovascular Disease

Conclusions about testosterone therapy and cardiovascular risk

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