madman
Super Moderator
Cardiovascular risk and testosterone – from subclinical atherosclerosis to lipoprotein function to heart failure
Abstract
The cardiovascular (CV) benefit and safety of treating low testosterone conditions is a matter of debate. Although testosterone deficiency has been linked to a rise in major adverse CV events, most of the studies on testosterone replacement therapy were not designed to assess CV risk and thus excluded men with advanced heart failure or recent history of myocardial infarction or stroke. Besides considering observational, interventional, and prospective studies, this review article evaluates the impact of testosterone on atherosclerosis process, including lipoprotein functionality, the progression of carotid intima-media thickness, inflammation, coagulation and thromboembolism, quantification of plaque volume, and vascular calcification. Until adequately powered studies evaluating testosterone effects in hypogonadal men at increased CV risk are available (TRAVERSE trial), clinicians should ponder the use of testosterone in men with atherosclerotic cardiovascular disease and discuss benefits and harms with the patients.
1 Introduction
Cardiovascular disease (CVD) is the leading cause of death worldwide, causing over 17 million premature deaths in 2016 [1]. The 2015 World Health Organization mortality registry has reported that CVD kills more women (55%) than men (45%), but the proportion of CV deaths before the age of 65 years is larger in men (30% compared to 26% in women) [2]. Atherosclerosis is a disease characterized by low-grade and chronic inflammation of the arterial wall which is triggered by subendothelial retention of plasma-derived apolipoprotein B (apoB)-containing lipoproteins in the inner layer of the arterial wall, the intima [3]. Besides this lipid-inflammatory etiology, advancing age is itself an established risk factor for CVD, being a component of all major lifetime risk estimate calculators [4, 5]. In view of the overall increase in life expectancy, evidence-based strategies to prevent CVD are needed in older people. This has drawn attention to the role of sex steroids, particularly testosterone, in cardiovascular health [6]. Declining testosterone levels in older men have been associated with the process of aging called “late-onset hypogonadism” (LOH), [7, 8] a clinical syndrome (usually associated with overweight/obesity requiring a specific rehabilitation) which results from failure of the testes to produce physiological concentrations of testosterone and/or a normal number of spermatozoa due to abnormalities at one or more sites of the hypothalamic-pituitary-testicular axis (HPT).
Testosterone deficiency has been generally linked to a rise in major adverse cardiovascular events (MACEs), especially myocardial infarction (MI) and stroke. However, whether testosterone replacement therapy is beneficial is still debated [9–11]. In 2010 the Food and Drug Administration (FDA) raised concerns on the potentially increased risk of CVD events upon testosterone administration after the premature interruption of the Testosterone in Older Men With Mobility Limitations (TOM) study [12]. Thus, in March 2015, all US commercial testosterone products underwent an FDA-mandated label change that restricted the prescription of these medications to men with hypogonadism of known etiology and included a warning about the risk of heart attacks and strokes [13].
Testosterone treatment has been associated with increased wellbeing and improved CV symptoms (angina, claudication). An extensive overview by Oskul et al [14] documented the benefit of testosterone in angina, with a raised mean time to 1-mm ST-segment depression on exercise stress testing from 309 seconds at baseline to 343 seconds after 4 weeks and 361 seconds after a 12-week treatment [15]. Intracoronary testosterone (10−10 to 10−7 mol/L) in non-hypogonadal men induced coronary vasodilatation of up to 4.5% compared to baseline [16]. A similar positive vasodilator activity was reported on brachial arteries following oral testosterone administration [17]. A number of potential mechanisms have been hypothesized, but there is clear evidence that the vasodilator activity is not linked to stimulated nitric oxide [18]. However, in peculiar conditions, as in the case of trans men undergoing hormone-affirming replacement therapy, exposure to testosterone may worsen endothelial function [19].
Finally, it should be considered that in men with coronary heart disease, testosterone deficiency seemed to be a relevant medical condition. As reported in a longitudinal study with a follow-up of 6.9±2.1 years, in men with vascular disease, testosterone deficiency was associated with premature death. Levels < 15.1 nmol/L corresponded to an HR of 1.86 (95%CI 1.1-3.2) for all-cause mortality and of 2.50 (95%CI 1.2-5.3) for vascular mortality [20].
*Considering that the CV benefit and safety of treating low testosterone conditions have not been definitely proven and controversies still persist, this review article focuses on these controversies and on the potential risks and benefits of testosterone supplementation on CV health.
Background reasons for the so-far inconclusive results among studies are (i) differences in dose regimens, (ii) insufficient statistical power for clinical events, or (iii) inclusion criteria allowing the recruitment of healthy asymptomatic men with low or low-normal testosterone. The effects of testosterone on atherosclerosis will be also reviewed in this context, including impact on platelet aggregation [21], high-density lipoproteins (HDL) functionality, and serum capacity to load macrophage with cholesterol [22].
2 Male hypogonadism: definition and classification
3 Impact of testosterone in atherosclerosis
3.1 Subclinical atherosclerosis
3.2 Lipoprotein functionality
3.3 Inflammation
3.4 Coagulation and thromboembolism
4 Testosterone replacement therapy and cardiovascular outcomes
4.1 Observational and retrospective studies
4.2 Interventional studies
4.3 A special condition: heart failure
4.4 Perspectives
5 Conclusion
Testosterone replacement therapy is commonly prescribed to men and it is, therefore, essential to gain more reliable safety data for CV outcomes from large and long-term studies. Testosterone replacement therapy is recommended only in symptomatic men with hypogonadism and consistently low serum total testosterone [10]. Nonetheless, the FDA mandated pharmaceutical companies to add labeling information about a possible increased risk of CV events, while the European Medicine Agency concluded that there is no consistent evidence of an increased CV risk associated with testosterone therapy in hypogonadal men [11]. While it appears that testosterone replacement therapy does not cause a marked increase in the risk of CV events, another meta-analysis clearly highlighted that none of the studies that evaluated to estimate the risk (15 pharmacoepidemiological and 93 RCT) had an enough long duration of exposure or were powered to exclude such a risk [128]. The 2020 clinical practice guideline by the American College of Physicians reached the same conclusion, i.e., most of the studies on testosterone replacement were not designed to assess CV risk and thus excluded men with advanced heart failure or a recent history of myocardial infarction or stroke [144].
On this matter, evaluating the lipid profile (e.g., HDL-C levels) would per se not be enough, rather, it is the functional capacity of lipoproteins that would need to be considered. Since lipid trafficking is a balance between cholesterol efflux and influx, in hypogonadal men proatherogenic lipoprotein-associated changes have been associated with lower cholesterol efflux and increased influx, thus offering an explanation for a potentially increased CV risk (Fig. 1) [22]. Testosterone has also been described as a risk factor for venous thromboembolism due to a rise in (i) hematocrit and blood viscosity, (ii) platelet aggregation, and (iii) thromboxane A2 concentrations in platelets. Whether or not this is a direct effect driven by testosterone supplementation or due to a rise in the levels of estrogens remains unclear [83].
Among other aspects that are worth consideration for testosterone treatment, there are changes in epicardial fat thickness. A rise was detected in subjects with hypogonadal Klinefelter Syndrome, similar to that found in obese age-matched euploid subjects [145]. The accumulation of epicardial fat represents, along with visceral fat, a major contributor to CVD risk, above and beyond BMI [146], possibly due to localized release of inflammatory adipokines [147].
Finally, it is worth mentioning that testosterone use is associated also with the regulation of ventricular repolarization by shortening the length of the QTc interval. A prolonged heart-rate QT is an independent predictor for cardiac, all-cause mortality [148], and torsades de points ventricular tachycardia [149]. Whether a high number of prolonged QT interval measurements were observed in hypogonadal men [150], the results from the TEAM trials showed that testosterone replacement attenuates the age-related increase in QT interval duration [151]. Similar conclusions were reached in men aged ≥ 65 in whom the transdermal administration of testosterone attenuates drug-induced QT lengthening [152]. However, although the precise mechanism linking testosterone and QT interval is poorly understood, the stimulation of endogenous human ether-a-go-go-related gene potassium channels seems one of the most reliable hypotheses [153].
Overall, clinicians must exercise prudence in the use of testosterone in men with prevalent atherosclerotic coronary and cerebrovascular disease. Testosterone replacement in symptomatic elderly men with low testosterone levels should benefit from an individualized approach where uncertainties, risks, and benefits of treatment can first be discussed with the patient.
Abstract
The cardiovascular (CV) benefit and safety of treating low testosterone conditions is a matter of debate. Although testosterone deficiency has been linked to a rise in major adverse CV events, most of the studies on testosterone replacement therapy were not designed to assess CV risk and thus excluded men with advanced heart failure or recent history of myocardial infarction or stroke. Besides considering observational, interventional, and prospective studies, this review article evaluates the impact of testosterone on atherosclerosis process, including lipoprotein functionality, the progression of carotid intima-media thickness, inflammation, coagulation and thromboembolism, quantification of plaque volume, and vascular calcification. Until adequately powered studies evaluating testosterone effects in hypogonadal men at increased CV risk are available (TRAVERSE trial), clinicians should ponder the use of testosterone in men with atherosclerotic cardiovascular disease and discuss benefits and harms with the patients.
1 Introduction
Cardiovascular disease (CVD) is the leading cause of death worldwide, causing over 17 million premature deaths in 2016 [1]. The 2015 World Health Organization mortality registry has reported that CVD kills more women (55%) than men (45%), but the proportion of CV deaths before the age of 65 years is larger in men (30% compared to 26% in women) [2]. Atherosclerosis is a disease characterized by low-grade and chronic inflammation of the arterial wall which is triggered by subendothelial retention of plasma-derived apolipoprotein B (apoB)-containing lipoproteins in the inner layer of the arterial wall, the intima [3]. Besides this lipid-inflammatory etiology, advancing age is itself an established risk factor for CVD, being a component of all major lifetime risk estimate calculators [4, 5]. In view of the overall increase in life expectancy, evidence-based strategies to prevent CVD are needed in older people. This has drawn attention to the role of sex steroids, particularly testosterone, in cardiovascular health [6]. Declining testosterone levels in older men have been associated with the process of aging called “late-onset hypogonadism” (LOH), [7, 8] a clinical syndrome (usually associated with overweight/obesity requiring a specific rehabilitation) which results from failure of the testes to produce physiological concentrations of testosterone and/or a normal number of spermatozoa due to abnormalities at one or more sites of the hypothalamic-pituitary-testicular axis (HPT).
Testosterone deficiency has been generally linked to a rise in major adverse cardiovascular events (MACEs), especially myocardial infarction (MI) and stroke. However, whether testosterone replacement therapy is beneficial is still debated [9–11]. In 2010 the Food and Drug Administration (FDA) raised concerns on the potentially increased risk of CVD events upon testosterone administration after the premature interruption of the Testosterone in Older Men With Mobility Limitations (TOM) study [12]. Thus, in March 2015, all US commercial testosterone products underwent an FDA-mandated label change that restricted the prescription of these medications to men with hypogonadism of known etiology and included a warning about the risk of heart attacks and strokes [13].
Testosterone treatment has been associated with increased wellbeing and improved CV symptoms (angina, claudication). An extensive overview by Oskul et al [14] documented the benefit of testosterone in angina, with a raised mean time to 1-mm ST-segment depression on exercise stress testing from 309 seconds at baseline to 343 seconds after 4 weeks and 361 seconds after a 12-week treatment [15]. Intracoronary testosterone (10−10 to 10−7 mol/L) in non-hypogonadal men induced coronary vasodilatation of up to 4.5% compared to baseline [16]. A similar positive vasodilator activity was reported on brachial arteries following oral testosterone administration [17]. A number of potential mechanisms have been hypothesized, but there is clear evidence that the vasodilator activity is not linked to stimulated nitric oxide [18]. However, in peculiar conditions, as in the case of trans men undergoing hormone-affirming replacement therapy, exposure to testosterone may worsen endothelial function [19].
Finally, it should be considered that in men with coronary heart disease, testosterone deficiency seemed to be a relevant medical condition. As reported in a longitudinal study with a follow-up of 6.9±2.1 years, in men with vascular disease, testosterone deficiency was associated with premature death. Levels < 15.1 nmol/L corresponded to an HR of 1.86 (95%CI 1.1-3.2) for all-cause mortality and of 2.50 (95%CI 1.2-5.3) for vascular mortality [20].
*Considering that the CV benefit and safety of treating low testosterone conditions have not been definitely proven and controversies still persist, this review article focuses on these controversies and on the potential risks and benefits of testosterone supplementation on CV health.
Background reasons for the so-far inconclusive results among studies are (i) differences in dose regimens, (ii) insufficient statistical power for clinical events, or (iii) inclusion criteria allowing the recruitment of healthy asymptomatic men with low or low-normal testosterone. The effects of testosterone on atherosclerosis will be also reviewed in this context, including impact on platelet aggregation [21], high-density lipoproteins (HDL) functionality, and serum capacity to load macrophage with cholesterol [22].
2 Male hypogonadism: definition and classification
3 Impact of testosterone in atherosclerosis
3.1 Subclinical atherosclerosis
3.2 Lipoprotein functionality
3.3 Inflammation
3.4 Coagulation and thromboembolism
4 Testosterone replacement therapy and cardiovascular outcomes
4.1 Observational and retrospective studies
4.2 Interventional studies
4.3 A special condition: heart failure
4.4 Perspectives
5 Conclusion
Testosterone replacement therapy is commonly prescribed to men and it is, therefore, essential to gain more reliable safety data for CV outcomes from large and long-term studies. Testosterone replacement therapy is recommended only in symptomatic men with hypogonadism and consistently low serum total testosterone [10]. Nonetheless, the FDA mandated pharmaceutical companies to add labeling information about a possible increased risk of CV events, while the European Medicine Agency concluded that there is no consistent evidence of an increased CV risk associated with testosterone therapy in hypogonadal men [11]. While it appears that testosterone replacement therapy does not cause a marked increase in the risk of CV events, another meta-analysis clearly highlighted that none of the studies that evaluated to estimate the risk (15 pharmacoepidemiological and 93 RCT) had an enough long duration of exposure or were powered to exclude such a risk [128]. The 2020 clinical practice guideline by the American College of Physicians reached the same conclusion, i.e., most of the studies on testosterone replacement were not designed to assess CV risk and thus excluded men with advanced heart failure or a recent history of myocardial infarction or stroke [144].
On this matter, evaluating the lipid profile (e.g., HDL-C levels) would per se not be enough, rather, it is the functional capacity of lipoproteins that would need to be considered. Since lipid trafficking is a balance between cholesterol efflux and influx, in hypogonadal men proatherogenic lipoprotein-associated changes have been associated with lower cholesterol efflux and increased influx, thus offering an explanation for a potentially increased CV risk (Fig. 1) [22]. Testosterone has also been described as a risk factor for venous thromboembolism due to a rise in (i) hematocrit and blood viscosity, (ii) platelet aggregation, and (iii) thromboxane A2 concentrations in platelets. Whether or not this is a direct effect driven by testosterone supplementation or due to a rise in the levels of estrogens remains unclear [83].
Among other aspects that are worth consideration for testosterone treatment, there are changes in epicardial fat thickness. A rise was detected in subjects with hypogonadal Klinefelter Syndrome, similar to that found in obese age-matched euploid subjects [145]. The accumulation of epicardial fat represents, along with visceral fat, a major contributor to CVD risk, above and beyond BMI [146], possibly due to localized release of inflammatory adipokines [147].
Finally, it is worth mentioning that testosterone use is associated also with the regulation of ventricular repolarization by shortening the length of the QTc interval. A prolonged heart-rate QT is an independent predictor for cardiac, all-cause mortality [148], and torsades de points ventricular tachycardia [149]. Whether a high number of prolonged QT interval measurements were observed in hypogonadal men [150], the results from the TEAM trials showed that testosterone replacement attenuates the age-related increase in QT interval duration [151]. Similar conclusions were reached in men aged ≥ 65 in whom the transdermal administration of testosterone attenuates drug-induced QT lengthening [152]. However, although the precise mechanism linking testosterone and QT interval is poorly understood, the stimulation of endogenous human ether-a-go-go-related gene potassium channels seems one of the most reliable hypotheses [153].
Overall, clinicians must exercise prudence in the use of testosterone in men with prevalent atherosclerotic coronary and cerebrovascular disease. Testosterone replacement in symptomatic elderly men with low testosterone levels should benefit from an individualized approach where uncertainties, risks, and benefits of treatment can first be discussed with the patient.
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