Effect of T on Cardiovascular Disease and Risk

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madman

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Authors of the paper from my hometown!




The Effect of Testosterone on Cardiovascular Disease and Cardiovascular Risk Factors in Males: A Review of Clinical and Pre-Clinical Data (2021)

Authors: Hargun Kaur, Geoff H. Werstuck, Ph.D.

*Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
*Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
*Department of Medicine, McMaster University, Hamilton, Ontario, Canada





Abstract

Cardiovascular disease (CVD) is the leading cause of death worldwide. The effects of testosterone, the primary male sex hormone, on cardiovascular risk have been of special interest due to the increased risk of CVD in males. While it is well-established that testosterone levels decline and cardiovascular mortality increases with age, the association between testosterone and CVD remains unclear. Observational and randomized studies on the effects of endogenous and exogenous testosterone have produced conflicting data and meta-analyses have been inconclusive, suggesting significant study heterogeneity. Despite a lack of adequately powered RCTs, large observational studies in the early 2010s led to advisories on the use of testosterone replacement therapy. Similar advisories have been mandated for certain types of androgen deprivation therapy. Additional research suggests that testosterone shortens the QTc interval, improves glycemic control, induces vasodilation, is pro-thrombotic, and has anti-obesity effects, while associations with atherosclerosis and inflammation are less clear. Despite inconclusive evidence on cardiovascular risk and inconsistencies among clinical practice guidelines, millions of males continue to use testosterone replacement and androgen deprivation therapy. In addition to summarizing clinical and pre-clinical data, this review provides insight on potential mechanisms of action of testosterone on CVD, applications of this knowledge to clinical settings, and avenues for future research.





Brief Summary

The effect of testosterone on cardiovascular disease has long been subject to debate. Observational and interventional studies have been conflicting and meta-analyses suggest significant heterogeneity and low-quality data. Research indicates that testosterone shortens the QTc interval, improves glycemic control, induces vasodilation, is pro-thrombotic, and has anti-obesity effects. This review summarizes existing data and provides insight on potential mechanisms of action of testosterone on CVD, applications to clinical settings, and avenues for future research.




Introduction

Cardiovascular disease (CVD) is the leading cause of death globally.1 Various factor increase the risk of CVD, including diabetes, obesity, hypertension, dyslipidemia, and increasing age. Epidemiological studies have suggested that males face an increased risk of CVD compared to females2 and evidence supports a role for sex hormones in the modulation of CVD pathogenesis in males and females. While the protective effect of estrogen on cardiovascular health is well-established, 3 the effect of testosterone is less clear.

An increased risk of premature cardiovascular events in males initially led to the belief that testosterone had detrimental effects on cardiovascular health. Some large observational and randomized studies have supported this conclusion, while others have suggested a cardioprotective role for testosterone. Systematic reviews and meta-analyses have generally reported low-quality evidence and hence have been inconclusive. With testosterone therapies being used in the treatment of conditions that affect millions of males worldwide,4 its relationship with cardiovascular risk and disease must be better understood to inform guidelines for their use. This review summarizes recent clinical and preclinical studies with the aim to better understand the effect, and possible mechanisms of action, of testosterone on cardiovascular risk. The effect of testosterone on specific cardiovascular risk factors will also be assessed.





Molecular Biology of Testosterone

Biosynthesis and Metabolism of Testosterone

Testosterone is the primary sex hormone in males. It is essential for the development of the male reproductive system and secondary sex characteristics. 5 Following stimulation by the luteinizing hormone (LH), testosterone is synthesized from cholesterol through steroidogenesis.5 This occurs primarily in testicular Leydig cells and, in smaller quantities, in the adrenal glands.5 Its synthesis is regulated by the hypothalamic-pituitary-testicular axis, with increasing testosterone levels activating a negative feedback loop that inhibits the release of gonadotropic releasing hormone (GnRH), follicle-stimulating hormone (FSH), and LH.6

Secreted testosterone circulates in the blood in its free form or bound to carrier proteins. Sex hormone-binding globulin (SHBG) is the major carrier protein of testosterone,6 with approximately 60% of testosterone bound to SHBG and an additional 40% bound to albumin.6 Only 1-2% of testosterone is unbound or free.7 Although only free testosterone was historically considered to be biologically available, albumin-bound testosterone is now also accepted as bioavailable, due to its lower binding affinity.7

Bioavailable testosterone can directly exert its effects on androgen receptors (AR). Alternatively, it may be metabolized to other steroid hormones, such as dihydrotestosterone (DHT) or 17β-estradiol (E2), by 5α-reductase and aromatase, respectively.5 DHT amplified the effects of testosterone as its highly active metabolite with a greater binding capacity and signaling induction potency. 6 In males, E2 is produced locally through conversion by aromatase,5 an enzyme expressed in multiple tissues including adipose tissue, bone, and brain.

Testosterone is largely metabolized to androsterone and aetiocholanolone and conjugated with glucuronic or sulphuric acid prior to excretion in the urine.6 After the age of 60, the metabolic clearance rate of testosterone decreases rapidly.8 Concurrently, with age, the levels of free and albumin-bound testosterone also declines, while SHBG-bound testosterone levels increase. 8 This results in decreased free testosterone levels and bioavailability. The effect of age on total testosterone concentration is not clear.



Physiological Effects of Testosterone

Most physiological effects of testosterone are mediated through its interaction with the AR, a ligand-dependant nuclear receptor. The AR gene spans eight exons and 90 kb at locus Xq11-12.9 It has three major functional domains each with a unique role in mediating the molecular mechanisms of androgens: N-terminal transcriptional regulatory domain, DNA-binding domain, and C-terminal ligand-binding domain. 10 While gene transcription is affected by cell type and age, the AR is expressed in most cell types and tissues, with the exception of the spleen.10

Androgens have diverse effects on multiple organ systems (Figure 1). These effects can occur through classical and non-classical mechanisms.11,12 Classical or DNA-binding dependant signaling involves androgen binding-induced conformational changes in the AR, which dissociate chaperone proteins and expose the AR nuclear location sequence.11 The AR/androgen complex then translocates to the nucleus and forms dimers that bind to specific androgen response promoter elements (ARE) to modulate gene transcription. 11 Non-classical or non-DNA-binding dependant signaling occurs within seconds or minutes and does not directly involve transcriptional changes. 12 While the specific mechanism is unclear, 2nd messenger pathway activation involving MAPK, Akt, and ERK has been implicated, as well as possible indirect gene repression through sequestration of transcription factors.12





Testosterone and Cardiovascular Risk

*Endogenous Testosterone Levels and Cardiovascular Risk

*Testosterone Replacement Therapy
Despite a lack of clarity on the relationship between endogenous testosterone and cardiovascular risk, testosterone replacement therapy (TRT) is widely used, especially in older males with low serum testosterone levels. TRT does have benefits such as improved sexual function, increased skeletal muscle mass, and increased bone mineral density.23 The Copenhagen Study Group conducted one of the first RCTs reporting increased mortality in males treated with testosterone, although the effect was not statistically significant (RR 1.17 [95% CI 0.65-2.15]).24 The infeasibility ―to demonstrate—in the foreseeable future—a beneficial effect of testosterone by continuing the study‖ led to the premature end of the trial.24 Despite this, testosterone sales increased 100-fold from the 1980s to 2010s, with a 40-fold in Canada from 2000 to 2011. 25

In the early 2010s, certain large observational and randomized studies found an increased cardiovascular risk to be associated with testosterone therapy. 26 In 2010, the Testosterone in Older Men (TOM) trial had to be stopped prematurely due to the increased incidence of cardiovascular events in the intervention group.26 The trial involved 209 elderly community-dwelling males with limited mobility, randomized to placebo or testosterone.26 Males in the highest quartile of testosterone levels were at elevated risk for cardiovascular events (HR 2.4; p = 0.05) compared to other subjects.26 Vigen et al.27 later conducted a retrospective cohort study to determine the effects of testosterone therapy in veterans undergoing coronary angiography with pre-existing low testosterone. Cox proportional hazard models indicated an increased risk of adverse cardiovascular outcomes in males receiving testosterone therapy (HR 1.29 [95% CI 1.04-1.58]).27 In accordance with these results, a retrospective cohort study by Finkle et al.28 reported a statistically significant elevation of myocardial infarction rates post-prescription of testosterone compared to pre-prescription, with an especially pronounced effect in males over the age of 75 (RR 3.43 [95% CI 1.54-7.66]). In males under 65, the excess risk was limited to those with a history of heart disease (RR 2.90 [95% CI 1.49-5.62]).28
Further supporting these results, the T Trials found a statistically significant 1-year increase in noncalcified plaque volume (estimated difference 41 mm3 [95% CI 14 to 67 mm3 ]) in hypogonadal elderly males receiving testosterone therapy compared to the placebo group. 29 no statistically significant difference was found in the number of cardiovascular events or calcified plaque progression between the intervention and control group.29

The indication of an association between testosterone therapy and risk for adverse cardiovascular events prompted the FDA to issue a safety warning on testosterone therapy for older males, which was followed by a reduction in testosterone prescriptions.30 The safety warning cautioned against the use of testosterone therapy for aging-related decline and reinforced the current approval of testosterone products for hypogonadal males only.30 However, it is important to note that the methodology and reliability of the aforementioned studies have since been questioned. The TOM Trials lacked predetermined cardiovascular endpoints as the trial was not designed to investigate cardiovascular health.26 Further, despite having a sample with a high prevalence of comorbidities, including hypertension, obesity, diabetes mellitus, and pre-existing CVD, only 4 major adverse cardiovascular events (MACE) occurred, although all were in the testosterone group.26 These results were not replicated in a later trial with a similar population and testosterone administration technique.31 Both Vigen et al.27 and Finkle et al.28 were retrospective in nature, which poses inherent design limitations that make it difficult to draw definitive conclusions from the data. Questions have also been raised with the methodological validity and statistical analysis techniques of Vigen et al.27

In contrast to these studies, others have reported a protective effect of testosterone therapy on cardiovascular health. Cheetham et al.32 found a lower risk of cardiovascular outcomes in androgen deficient males who had received TRT (HR 0.67 [95% CI 0.62-0.73]), analyzed retrospectively for a median of 3.4 years. In a recent matched cohort study, short-term testosterone therapy increased the risk of mortality and cardiovascular events in males over the age of 65, while longer-term therapy was associated with reduced risk of mortality, adverse cardiovascular events, and prostate cancer.33

As a result of these conflicting results, a recent meta-analysis found no significant association between testosterone therapy and cardiovascular events and mortality and reported low-quality evidence due to bias, inconsistencies, and imprecision.34 This has led to inconsistencies between clinical practice guidelines. While all acknowledge the possible cardiovascular risks of testosterone therapy, there is disagreement on the minimum amount of time following a major cardiovascular event that an individual may receive testosterone therapy.35

*Adequately powered randomized clinical trials designed to assess cardiovascular events are required to definitively determine the effect of testosterone therapy on cardiovascular risk. The TRAVERSE trial is an ongoing clinical trial designed to measure the time to MACE in hypogonadal males, aged 45 to 80 years, with increased risk or evidence of CVD. 36 The study commenced in May 2018 and is expected to be complete in June 2022, with 6000 planned participants randomized to topical testosterone or placebo.36 This clinical trial will play an important role in determining the safety of TRT in hypogonadal males.



*Androgen Deprivation Therapy




Molecular Mechanisms of the Action of Testosterone on Cardiovascular Risk Factors

*The Effect of Testosterone on Cardiovascular Physiology

*The Association of Testosterone with Atherosclerosis and Thrombosis

*The Association of Testosterone with Diabetes


*The Association of Testosterone with Obesity

*The Association of Testosterone with Inflammation


*The Interplay Between Testosterone and Physical Activity




Conclusion and Future Directions


Given the prevalence and morbidity of CVD, it is important to clarify potential risk factors, especially in males as they face higher cardiovascular risk than females. Testosterone, the major sex hormone in males, has been a primary candidate in studies of cardiovascular risk. Despite decades of research on the topic, clinical and pre-clinical data on the effects of exogenous and endogenous testosterone have produced contradictory and/or inconclusive results. In spite of this lack of clarity, many males are currently undergoing testosterone replacement or androgen deprivation therapy.

It is thus imperative to conduct adequately powered RCTs, such as the TRAVERSE36 and PRONOUNCE58 trials, designed to study the effect of testosterone on cardiometabolic health to conclusively determine the cardiovascular effects and safety of associated therapies. While these trials are assessing outcomes in males with hypogonadism and prostate cancer, it is also important to study effects in older males without these conditions, as they have an increased likelihood of using testosterone therapies. Although this review is primarily focused on the role of testosterone in males, possible differential effects of the hormone in females must be considered in future studies. Moreover, there must be further investigation into the mechanisms of action of testosterone. In the meantime, however, it is important for patients to be advised of the possible cardiovascular risk associated with testosterone therapies and encouraged to make informed decisions while being mindful of study limitations.
 

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madman

Super Moderator
Figure 1. Physiological Effects of Testosterone. Testosterone has effects on multiple organs, many of which have direct and/or indirect implications on cardiovascular health * indicates inconclusive research on the specific effect.
Screenshot (6306).png
 

madman

Super Moderator
Figure 2. Biochemical Pathway of Testosterone. Testosterone, synthesized from cholesterol following LH stimulation, travels through the bloodstream from Leydig cells to target cells. Testosterone can be converted to DHT or E2. Testosterone and DHT bind to the AR to regulate androgen-responsive genes. Testosterone can also act via non-genomic pathways. AR: androgen receptor, ARE: androgen response element. CR: coregulator, ER: estrogen receptor, HSP: heat shock protein, SHBG: sex-hormone binding globulin, T: testosterone.
Screenshot (6307).png
 

madman

Super Moderator
Figure 3. Effect of Testosterone on Cardiovascular Risk. Graphical depiction of the hypothesized mechanisms of action of testosterone on various cardiovascular risk factors.* indicates research in the area is inconclusive. <-> indicates a likely bidirectional relationship.
Screenshot (6309).png
 

madman

Super Moderator
*Adequately powered randomized clinical trials designed to assess cardiovascular events are required to definitively determine the effect of testosterone therapy on cardiovascular risk. The TRAVERSE trial is an ongoing clinical trial designed to measure the time to MACE in hypogonadal males, aged 45 to 80 years, with increased risk or evidence of CVD. 36 The study commenced in May 2018 and is expected to be complete in June 2022, with 6000 planned participants randomized to topical testosterone or placebo.36 This clinical trial will play an important role in determining the safety of TRT in hypogonadal males.
 

DorianGray

Active Member
While it is well-established that testosterone levels decline and cardiovascular mortality increases with age, the association between testosterone and CVD remains unclear...

Will be interesting to see the data from the TRAVERSE study. The interplay between various CVD factors and use of TRT intrigues me. For example, I've observed changes in how cholesterol levels, and apolipoprotein B have changed for me on and off TRT. Other things like carotid intima-media thickness (CIMT) and plaque thickness, endothelial glycocalyx integrity and LDL particle size, etc. and how they change with TRT and affect CVD potential also come to mind.
Perhaps TRT produces beneficial effects on some parameters while taking away from others. And damn statins, positive and negative. I think cardiovascular health is of utmost importance. TRT may not compromise it (once all the clues are in) but it may not be of any benefit either.
 

Vince

Super Moderator
While it is well-established that testosterone levels decline and cardiovascular mortality increases with age, the association between testosterone and CVD remains unclear...

Will be interesting to see the data from the TRAVERSE study. The interplay between various CVD factors and use of TRT intrigues me. For example, I've observed changes in how cholesterol levels, and apolipoprotein B have changed for me on and off TRT. Other things like carotid intima-media thickness (CIMT) and plaque thickness, endothelial glycocalyx integrity and LDL particle size, etc. and how they change with TRT and affect CVD potential also come to mind.
Perhaps TRT produces beneficial effects on some parameters while taking away from others. And damn statins, positive and negative. I think cardiovascular health is of utmost importance. TRT may not compromise it (once all the clues are in) but it may not be of any benefit either.
I never noticed testosterone hurting my LDL particle numbers or size. I did notice it on nandrolone, it destroyed my LDL particles, made them small and increase the number. But my standard LDL lab, looked the same.
 
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