madman
Super Moderator
New Horizons: Testosterone or Exercise for Cardiometabolic Health in Older Men (2023)
Daniel J Green, Lauren C Chasland, Louise H Naylor, Bu B Yeap
Abstract
Middle-aged and older men have typically accumulated comorbidities, are increasingly sedentary, and have lower testosterone concentrations (T) compared to younger men. Both reduced physical activity (PA) and lower T are associated with, and may predispose to, metabolically adverse changes in body composition, which contribute to higher risks of cardiometabolic disease. Exercise improves cardiometabolic health, but sustained participation is problematic. By contrast, rates of T prescription have increased, particularly in middle-aged and older men without organic diseases of the hypothalamus, pituitary, or testes, reflecting the unproven concept of a restorative hormone that preserves health. Two recent large randomized trials of T, and meta-analyses of randomized trials, did not show a signal for adverse cardiovascular (CV) events, and T treatment on a background of lifestyle intervention reduced type 2 diabetes by 40% in men at high risk. Men with both higher endogenous T and higher PA levels have lower CV risk, but causality remains unproven. Exercise training interventions improve blood pressure and endothelial function in middle-aged and older men, without comparable benefits or additive effects of T treatment. Therefore, exercise training improves cardiometabolic health in middle-aged and older men when effectively applied as a supervised regimen incorporating aerobic and resistance modalities. Treatment with T may have indirect cardiometabolic benefits, mediated via favorable changes in body composition. Further evaluation of testosterone as a pharmacological intervention to improve cardiometabolic health in aging men could consider longer treatment durations and combination with targeted exercise programs.
Introduction
Physical inactivity is now considered a key risk factor for non-communicable diseases and the fourth leading cause of death worldwide (1). There is clear evidence of an inverse linear dose-response relationship between physical activity (PA) volume and all-cause mortality (2), with the greatest improvements in cardiovascular (CV) risk occurring when moving from being sedentary to engaging in low levels of activity (3). One prospective cohort study (n=416,175) reported a 14% decrease in all-cause mortality and 3-year longer life expectancy in those who engaged in 15 mins of daily physical activity, compared to those being inactive (4). Moreover, the lower all-cause mortality associated with moderate levels of PA may be more apparent in older (60-74 years, - 34%) than younger adults (35-59 years, -26%) (5), and recent studies utilizing wearable technologies suggest a greater decrease in all-cause mortality than historical studies which relied upon self-report (6). The beneficial influence of physical activity may be mediated by improvements in cardiorespiratory fitness and indices of vascular health such as blood pressure (BP) and endothelial function, and via exercise-induced increases in muscle mass, strength, or functions. Nonetheless, increasing PA remains a population health challenge (7), and pharmacological strategies that emulate the impacts of exercise have recently been mooted.
Testosterone (T) plays an important role in sexual development, behavior, and body composition, and symptoms of androgen deficiency include decreased energy levels, low sexual desire, low mood, irritability, poor concentration, and reduced muscle mass and strength (8,9). Testosterone is the classical anabolic hormone that, like resistance exercise, acts to increase muscle mass (10). Greater muscle mass protects against the development of sarcopenia and frailty and also confers metabolic benefits. Transgenic mice expressing a constitutively active protein kinase, Akt1, which stimulates muscle hypertrophy via the growth of type IIb muscle fibers, exhibit reduced fat accumulation and increased metabolic rate, hepatic fatty acid oxidation, and ketone body production (11). Furthermore, mice with a null mutation of myostatin, an endogenous inhibitor of muscle growth, are resistant to diet-induced obesity and have markedly improved insulin sensitivity (12). Highlighting the metabolic importance of muscle mass, a monoclonal antibody targeting the activin type II receptor to facilitate skeletal muscle growth, increased lean mass, reduced fat mass, and improved glycemia in a phase 2 trial of people with diabetes (13).
T treatment has become increasingly prevalent in recent decades (14), but the safety of its use beyond men with pathological androgen deficiency remains unclear. Nonetheless, T prescription has increased 11-fold in recent decades, partly due to the unproven premise of a restorative health-preserving hormone (14). Non-medically prescribed and off-label use may also occur, with some middle-aged and older men considering T supplementation an anti-aging strategy 15). Interestingly, although T concentrations can decrease with age (16,17), they are higher in older men who engage in a healthy lifestyle, inclusive of regular exercise, compared to men who have less healthy lifestyles (18). The influence of higher endogenous circulating T concentrations, and the effects of pharmacological intervention with exogenous T treatment, on cardiometabolic health in middle-aged and older men are pivotal to a better understanding of the endocrinologies of male aging (19). An equally important question is whether a combination of T treatment with exercise training might achieve optimal cardiometabolic outcomes in aging men.
*This review compares the independent, and possible combined, effects of T and exercise on cardiometabolic health and longevity in men. It considers the impacts of these factors from an epidemiological perspective, and in terms of their effects on physiological outcomes such as blood pressure and vascular function, as demonstrated in randomized trials. The consequences of anabolic steroid abuse are beyond the scope of this review.
Is Endogenous Testosterone Associated with Cardiometabolic Health?
*Thus, lower endogenous T concentrations may be related to all-cause rather than cardiovascular 14 mortality risk, but the non-linear nature of the association merits consideration and causality 15 remains unproven.
Does Exogenous Testosterone Treatment Impact Cardiometabolic Health?
*Whilst not the primary focus of this review, erythrocytosis, and elevation of hematocrit are recognized adverse events related to T treatment (9,59,61,76,77). The presence of prostate cancer is a contraindication of T therapy (8,9). Evidence to date suggests that T treatment does not increase the risk of developing prostate cancer beyond that expected in eugonadal men, but it may be associated with the detection of subclinical prostate cancer via PSA testing and prostate biopsy (8,9,59,61,63,77). The overall frequency of serious adverse events including prostate cancer events and MACE in large RCTs has been reassuringly low, albeit such trials, including T Trials and T4DM, generally excluded men at very high risk (44,49,50,63). The only T RCT powered to examine CV events as a primary endpoint, the “TRAVERSE” study, recruited hypogonadal men aged 45-80 years with T <300 ng/dL (10.4 nmol/L) with evidence of CVD or at increased risk for CVD (78). It commenced in 2018 and was completed in November 2022 with 5,246 participants (79). Its results will provide vital information for both cardiovascular and prostate safety of T therapy.
Are Higher Levels of Physical Activity and/or Exercise Associated with Better Cardiovascular Outcomes?
*Collectively, these results highlight the impact of PA on CV risk and all-cause mortality in middle and older age. The feasibility of implementing lifestyle interventions in sedentary older adults was demonstrated in the LIFE Study, in which 818 participants randomized to a moderate intensity structured physical activity program had a lower risk of major mobility disability compared to 817 who received a health education program, over a mean follow-up of 2.6 years (93).
Do Testosterone and Exercise Have Additive Effects on Cardiometabolic Health in 15 Aging Men?
*While outside the scope of this review, it is also possible that higher T concentrations or treatment with T, combined with higher PA levels, may have additional potential benefits on sexual and physical function, and wellbeing (61,63). Important gaps exist in our understanding of the interrelationships between T concentrations, physical in/activity, and cardiovascular risk. We now consider what is known about the impact of testosterone, exercise, and their combination on key measures of cardiovascular risk, namely blood pressure and vascular health and function.
What Are the Effects of Testosterone, Exercise, and Their Combination on Blood Pressure?
High blood pressure (BP) is recognized as a leading risk factor for mortality, responsible for 13% of deaths globally (1). The prevalence of hypertension increases with age, and it is forecast to affect more than 1.5 billion people worldwide by 2025 (100,101). A 2 mmHg lower office systolic BP (SBP) has been associated with a 10% lower risk of stroke and a 7% lower risk of ischemic heart disease, in primarily middle-aged adults (102)
What Impact Does T Have on Blood Pressure?
- Traditional single-measurement “office” blood pressure
- Ambulatory (24-hr) blood pressure
What Impact Does Exercise Training Have on Blood Pressure?
-Traditional office blood pressure
- Ambulatory (24-hr) blood pressure
What Impact Does the Combination of T Treatment and Exercise Training Have on Blood Pressure?
*BP should be carefully assessed and monitored when prescribing T treatment to middle-aged and older men. Conversely, middle-aged and older men with low-normal T concentrations with higher-than-optimal BP could benefit from a suitable exercise program.
What are the Effects of Testosterone, Exercise, and Their Combination on Vascular Function?
What is Vascular Function and How is it Assessed?
What Impact does Testosterone Have on Vascular Function?
-Endothelium-dependent dilation
-Endothelium-independent dilation
What Impact Does Exercise Training Have on Vascular Health and Function?
-Endothelium-dependent dilation
-Endothelium-independent dilation
Does the Combination of Exercise Training and Testosterone Have Additive Impacts on Vascular Health and Function?
*In summary, the effect of T treatment alone on vascular function in middle-aged and older men is unclear, with inconsistent results reported for both endothelium-dependent and -independent dilation. In contrast, there is a mature body of evidence supporting the effect of exercise on vascular health and function (174,175). Whether the combination of T treatment and an exercise program provides benefits beyond that experienced with exercise alone has not been widely studied. However, the evidence that is available indicates that exercise is beneficial for vascular, and in particular endothelial, function whereas short-term T administration does not confer benefits, or provide any additional effect in addition to the impact of exercise per se.
Conclusions
Often in parallel with declining T concentrations, aging men may experience decreases in fitness, strength, and vascular function; all of which are associated with increased mortality (191-193). From an epidemiological perspective, having higher endogenous T concentrations and engaging in higher levels of PA are associated with more favorable cardiometabolic outcomes in men. From a clinical perspective, exercise interventions are of undoubted benefit, but require effective implementations and sustained adherence. The effects of T pharmacotherapy in men who do not have organic hypogonadism on cardiometabolic outcomes require further study. Such T intervention may be more effective if sustained over a period of time and if administered in conjunction with lifestyle interventions (as in T4DM), or tailored exercise programs. It is possible that the cardiometabolic benefits of T may be indirect, reflecting changes in body composition, rather than directly improving BP or endothelial function. Exercise remains a first-line strategy for aging men to improve their cardiometabolic health.
Daniel J Green, Lauren C Chasland, Louise H Naylor, Bu B Yeap
Abstract
Middle-aged and older men have typically accumulated comorbidities, are increasingly sedentary, and have lower testosterone concentrations (T) compared to younger men. Both reduced physical activity (PA) and lower T are associated with, and may predispose to, metabolically adverse changes in body composition, which contribute to higher risks of cardiometabolic disease. Exercise improves cardiometabolic health, but sustained participation is problematic. By contrast, rates of T prescription have increased, particularly in middle-aged and older men without organic diseases of the hypothalamus, pituitary, or testes, reflecting the unproven concept of a restorative hormone that preserves health. Two recent large randomized trials of T, and meta-analyses of randomized trials, did not show a signal for adverse cardiovascular (CV) events, and T treatment on a background of lifestyle intervention reduced type 2 diabetes by 40% in men at high risk. Men with both higher endogenous T and higher PA levels have lower CV risk, but causality remains unproven. Exercise training interventions improve blood pressure and endothelial function in middle-aged and older men, without comparable benefits or additive effects of T treatment. Therefore, exercise training improves cardiometabolic health in middle-aged and older men when effectively applied as a supervised regimen incorporating aerobic and resistance modalities. Treatment with T may have indirect cardiometabolic benefits, mediated via favorable changes in body composition. Further evaluation of testosterone as a pharmacological intervention to improve cardiometabolic health in aging men could consider longer treatment durations and combination with targeted exercise programs.
Introduction
Physical inactivity is now considered a key risk factor for non-communicable diseases and the fourth leading cause of death worldwide (1). There is clear evidence of an inverse linear dose-response relationship between physical activity (PA) volume and all-cause mortality (2), with the greatest improvements in cardiovascular (CV) risk occurring when moving from being sedentary to engaging in low levels of activity (3). One prospective cohort study (n=416,175) reported a 14% decrease in all-cause mortality and 3-year longer life expectancy in those who engaged in 15 mins of daily physical activity, compared to those being inactive (4). Moreover, the lower all-cause mortality associated with moderate levels of PA may be more apparent in older (60-74 years, - 34%) than younger adults (35-59 years, -26%) (5), and recent studies utilizing wearable technologies suggest a greater decrease in all-cause mortality than historical studies which relied upon self-report (6). The beneficial influence of physical activity may be mediated by improvements in cardiorespiratory fitness and indices of vascular health such as blood pressure (BP) and endothelial function, and via exercise-induced increases in muscle mass, strength, or functions. Nonetheless, increasing PA remains a population health challenge (7), and pharmacological strategies that emulate the impacts of exercise have recently been mooted.
Testosterone (T) plays an important role in sexual development, behavior, and body composition, and symptoms of androgen deficiency include decreased energy levels, low sexual desire, low mood, irritability, poor concentration, and reduced muscle mass and strength (8,9). Testosterone is the classical anabolic hormone that, like resistance exercise, acts to increase muscle mass (10). Greater muscle mass protects against the development of sarcopenia and frailty and also confers metabolic benefits. Transgenic mice expressing a constitutively active protein kinase, Akt1, which stimulates muscle hypertrophy via the growth of type IIb muscle fibers, exhibit reduced fat accumulation and increased metabolic rate, hepatic fatty acid oxidation, and ketone body production (11). Furthermore, mice with a null mutation of myostatin, an endogenous inhibitor of muscle growth, are resistant to diet-induced obesity and have markedly improved insulin sensitivity (12). Highlighting the metabolic importance of muscle mass, a monoclonal antibody targeting the activin type II receptor to facilitate skeletal muscle growth, increased lean mass, reduced fat mass, and improved glycemia in a phase 2 trial of people with diabetes (13).
T treatment has become increasingly prevalent in recent decades (14), but the safety of its use beyond men with pathological androgen deficiency remains unclear. Nonetheless, T prescription has increased 11-fold in recent decades, partly due to the unproven premise of a restorative health-preserving hormone (14). Non-medically prescribed and off-label use may also occur, with some middle-aged and older men considering T supplementation an anti-aging strategy 15). Interestingly, although T concentrations can decrease with age (16,17), they are higher in older men who engage in a healthy lifestyle, inclusive of regular exercise, compared to men who have less healthy lifestyles (18). The influence of higher endogenous circulating T concentrations, and the effects of pharmacological intervention with exogenous T treatment, on cardiometabolic health in middle-aged and older men are pivotal to a better understanding of the endocrinologies of male aging (19). An equally important question is whether a combination of T treatment with exercise training might achieve optimal cardiometabolic outcomes in aging men.
*This review compares the independent, and possible combined, effects of T and exercise on cardiometabolic health and longevity in men. It considers the impacts of these factors from an epidemiological perspective, and in terms of their effects on physiological outcomes such as blood pressure and vascular function, as demonstrated in randomized trials. The consequences of anabolic steroid abuse are beyond the scope of this review.
Is Endogenous Testosterone Associated with Cardiometabolic Health?
*Thus, lower endogenous T concentrations may be related to all-cause rather than cardiovascular 14 mortality risk, but the non-linear nature of the association merits consideration and causality 15 remains unproven.
Does Exogenous Testosterone Treatment Impact Cardiometabolic Health?
*Whilst not the primary focus of this review, erythrocytosis, and elevation of hematocrit are recognized adverse events related to T treatment (9,59,61,76,77). The presence of prostate cancer is a contraindication of T therapy (8,9). Evidence to date suggests that T treatment does not increase the risk of developing prostate cancer beyond that expected in eugonadal men, but it may be associated with the detection of subclinical prostate cancer via PSA testing and prostate biopsy (8,9,59,61,63,77). The overall frequency of serious adverse events including prostate cancer events and MACE in large RCTs has been reassuringly low, albeit such trials, including T Trials and T4DM, generally excluded men at very high risk (44,49,50,63). The only T RCT powered to examine CV events as a primary endpoint, the “TRAVERSE” study, recruited hypogonadal men aged 45-80 years with T <300 ng/dL (10.4 nmol/L) with evidence of CVD or at increased risk for CVD (78). It commenced in 2018 and was completed in November 2022 with 5,246 participants (79). Its results will provide vital information for both cardiovascular and prostate safety of T therapy.
Are Higher Levels of Physical Activity and/or Exercise Associated with Better Cardiovascular Outcomes?
*Collectively, these results highlight the impact of PA on CV risk and all-cause mortality in middle and older age. The feasibility of implementing lifestyle interventions in sedentary older adults was demonstrated in the LIFE Study, in which 818 participants randomized to a moderate intensity structured physical activity program had a lower risk of major mobility disability compared to 817 who received a health education program, over a mean follow-up of 2.6 years (93).
Do Testosterone and Exercise Have Additive Effects on Cardiometabolic Health in 15 Aging Men?
*While outside the scope of this review, it is also possible that higher T concentrations or treatment with T, combined with higher PA levels, may have additional potential benefits on sexual and physical function, and wellbeing (61,63). Important gaps exist in our understanding of the interrelationships between T concentrations, physical in/activity, and cardiovascular risk. We now consider what is known about the impact of testosterone, exercise, and their combination on key measures of cardiovascular risk, namely blood pressure and vascular health and function.
What Are the Effects of Testosterone, Exercise, and Their Combination on Blood Pressure?
High blood pressure (BP) is recognized as a leading risk factor for mortality, responsible for 13% of deaths globally (1). The prevalence of hypertension increases with age, and it is forecast to affect more than 1.5 billion people worldwide by 2025 (100,101). A 2 mmHg lower office systolic BP (SBP) has been associated with a 10% lower risk of stroke and a 7% lower risk of ischemic heart disease, in primarily middle-aged adults (102)
What Impact Does T Have on Blood Pressure?
- Traditional single-measurement “office” blood pressure
- Ambulatory (24-hr) blood pressure
What Impact Does Exercise Training Have on Blood Pressure?
-Traditional office blood pressure
- Ambulatory (24-hr) blood pressure
What Impact Does the Combination of T Treatment and Exercise Training Have on Blood Pressure?
*BP should be carefully assessed and monitored when prescribing T treatment to middle-aged and older men. Conversely, middle-aged and older men with low-normal T concentrations with higher-than-optimal BP could benefit from a suitable exercise program.
What are the Effects of Testosterone, Exercise, and Their Combination on Vascular Function?
What is Vascular Function and How is it Assessed?
What Impact does Testosterone Have on Vascular Function?
-Endothelium-dependent dilation
-Endothelium-independent dilation
What Impact Does Exercise Training Have on Vascular Health and Function?
-Endothelium-dependent dilation
-Endothelium-independent dilation
Does the Combination of Exercise Training and Testosterone Have Additive Impacts on Vascular Health and Function?
*In summary, the effect of T treatment alone on vascular function in middle-aged and older men is unclear, with inconsistent results reported for both endothelium-dependent and -independent dilation. In contrast, there is a mature body of evidence supporting the effect of exercise on vascular health and function (174,175). Whether the combination of T treatment and an exercise program provides benefits beyond that experienced with exercise alone has not been widely studied. However, the evidence that is available indicates that exercise is beneficial for vascular, and in particular endothelial, function whereas short-term T administration does not confer benefits, or provide any additional effect in addition to the impact of exercise per se.
Conclusions
Often in parallel with declining T concentrations, aging men may experience decreases in fitness, strength, and vascular function; all of which are associated with increased mortality (191-193). From an epidemiological perspective, having higher endogenous T concentrations and engaging in higher levels of PA are associated with more favorable cardiometabolic outcomes in men. From a clinical perspective, exercise interventions are of undoubted benefit, but require effective implementations and sustained adherence. The effects of T pharmacotherapy in men who do not have organic hypogonadism on cardiometabolic outcomes require further study. Such T intervention may be more effective if sustained over a period of time and if administered in conjunction with lifestyle interventions (as in T4DM), or tailored exercise programs. It is possible that the cardiometabolic benefits of T may be indirect, reflecting changes in body composition, rather than directly improving BP or endothelial function. Exercise remains a first-line strategy for aging men to improve their cardiometabolic health.
