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Relationships between endogenous and exogenous testosterone and cardiovascular disease in men (2022)
Arthi Thirumalai · Bradley D. Anawalt
Abstract
In this narrative review, we discuss the evidence about the controversy about the cardiovascular effects of endogenous and exogenous testosterone in men. Prospective cohort studies with follow-ups of~5–15 years generally indicate no association or a possible inverse relationship between serum endogenous testosterone concentrations and composite major cardiovascular events, cardiovascular deaths, and overall mortality. Pharmacoepidemiological studies of large databases generally show no association between testosterone therapy and incident major cardiovascular events, and some pharmacoepidemiological studies demonstrate an association with decreased overall mortality. Randomized, placebo-controlled trials indicate that there is no increased incidence of overall major cardiovascular events with 1–3 years of testosterone therapy. These placebo-controlled trials have major limitations including small numbers of participants, short duration of testosterone therapy and follow-up, and lack of systematic adjudication of cardiovascular events. Overall, the evidence indicates that endogenous testosterone concentrations and testosterone therapy at physiological dosages confer no or minimal effects on the incidence of cardiovascular outcomes. There is insufficient evidence to make conclusions about testosterone therapy for patients at high risk of cardiovascular events (e.g., men with recent myocardial infarctions or stroke and men with recurrent idiopathic deep venous thromboses). In general, clinicians should avoid prescribing supraphysiological testosterone therapy to hypogonadal men or men with slightly low to low-normal serum testosterone concentrations and no identified disorder of the hypothalamus-pituitary-testicular axis because of the uncertain cardiovascular risks and the lack of proven health benefits. For most men with bona fide hypogonadism, the benefits of testosterone therapy exceed the potential risk of adverse cardiovascular effects.
Introduction
One of the raging controversies in the field of reproductive endocrinology is the role of sex hormones in the pathophysiology of cardiovascular disease and whether testosterone and estrogen increase or decrease the risk of cardiovascular events in humans. More is known about the effects of sex steroid hormones and cardiovascular risk in women than in men, and the lessons learned from randomized controlled trials in women are instructive to the nascent research and clinical care of men. It is important to understand the history of the anecdotal basis for the original simplistic hypotheses that “estrogen is good for the heart” and “testosterone is bad for the heart” for women and for men. The past three decades of women’s health research have demonstrated and reinforced two key concepts: 1) epidemiological studies are typically best suited for the development of hypotheses and require a randomized controlled trial for confirmation of these hypotheses; and 2) there are no simple conclusions about the effects of sex steroid hormones on cardiovascular risk: estrogen is not a cardiovascular panacea nor is testosterone a cardiovascular toxin. Although research on the effects of sex steroids on cardiovascular risk in men has lagged decades behind research on this topic in women, the same lessons seem to apply. We briefly review the poor evidence that stimulated the simplistic (and erroneous) polemical hypotheses that estrogen is beneficial and testosterone is detrimental to human cardiovascular health. We will also briefly review the key studies of the effects of sex steroid hormones on cardiovascular risk in women to provide context for the research of men that has been largely based on epidemiology studies.
In this narrative review, we summarize the findings of a large number of epidemiological studies and the scanty evidence from randomized clinical trials of the effects of testosterone and its major metabolites (estradiol and dihydrotestosterone) on cardiovascular outcomes in men (Fig. 1). This reviewed a search of PubMed from January 1, 2000, to March 1, 2022, and Google Scholar using the terms “testosterone and stroke”, “testosterone and myocardial infarction” “testosterone and cardiovascular disease”, “testosterone and deep venous thrombosis”, “testosterone and pulmonary embolism”, “hypogonadism and cardiovascular disease”, “hypogonadism and myocardial infarction”, and “hypogonadism and stroke”. In addition, we scanned the reference section of articles derived from the above search to retrieve additional salient articles.
In men, as with women, there is a distinction between the potential risks and benefits of naturally occurring endogenous concentrations of sex steroid hormone concentrations and testosterone therapy. There is also an important distinction between sex steroid hormone replacement therapy at physiological or near-physiological dosages in hypogonadal men and women (e.g., a premenopausal woman with gonadotropin deficiency due to a pituitary macroadenoma) versus sex steroid hormone therapy for a man without hypogonadism due to an identified disorder of the hypothalamus-pituitary-testicular axis or sex steroid hormone therapy for a postmenopausal woman. We use the cautionary lessons learned from sex hormone studies in women and the current evidence in men to make conclusions and clinical recommendations about testosterone therapy for male hypogonadism.
2 Serum sex steroid hormone concentrations and risk of cardiovascular events in women
2.1 Sex steroid hormone therapy and cardiovascular risk in postmenopausal women
In summary, there were early, biased observations by renowned clinicians that suggested that men are at a greatly higher risk of cardiovascular disease than women and led to the general hypotheses that estrogen is “good” for cardiovascular health and testosterone is “bad” for cardiovascular health. However, the most recent epidemiological data indicate that there are small differences in the overall incidence of cardiovascular disease between men and women and that these differences vary based on the specific cardiovascular disorder and the age cohort of the men and women [3]. In addition, the estrogen treatment trials of menopausal women have yielded complex results that belie a simple conclusion that estrogen is uniformly “good” or “bad” for postmenopausal women who have the highest risk of cardiovascular disease and cardiovascular death.
3 Endogenous serum sex steroid hormone concentrations and cardiovascular outcomes in men
3.1 Prospective immunoassay cohort studies of serum endogenous sex hormones and overall cardiovascular risk and mortality in men
3.2 Prospective mass spectrometry cohort studies of serum endogenous sex hormones and overall cardiovascular risk and mortality in men
3.3 Possible reverse causality between endogenous serum testosterone concentrations and overall cardiovascular risk and mortality in men
3.4 Summary of epidemiology of serum endogenous sex hormone concentrations and incident overall cardiovascular risk and mortality in men
The epidemiological data suggest that endogenous serum testosterone, DHT, and estradiol concentrations are not highly associated with future incident risk of overall cardiovascular events, cardiovascular mortality, or all-cause mortality. Although some studies show an inverse association between baseline serum concentrations of testosterone, DHT, and estradiol, with incident risk of major cardiovascular events and/or overall mortality, there is no consistent pattern among the prospective cohort studies. In addition, this inverse association might be due to reverse causality because older men with higher body mass indices or waist circumferences and multiple morbidities have lower serum testosterone concentrations and higher incident risk of major cardiovascular events and all-cause mortality.
4 Low serum testosterone due to therapeutic suppression in men: increased overall cardiovascular risk and mortality?
Although androgen deprivation therapy for the treatment of prostate cancer is associated with metabolic syndrome, adverse effects of body composition, and increased incident risk of myocardial infarction and venothromboembolic events, the causal relationship has not been proven [40, 41]. An equally plausible hypothesis is that men with more advanced prostate cancer that is treated with androgen deprivation therapy tend to have worse general health and a higher risk of major cardiovascular outcomes than the control comparator groups in the published epidemiological studies [40].
5 Testosterone therapy and overall cardiovascular risk and mortality in men
In summary, the data from pharmaco-epidemiological studies are mixed, but the majority of the studies demonstrate no association between testosterone therapy and incident risk of major cardiovascular events. The limited data from modest-sized randomized clinical trials for testosterone replacement therapy at typical physiological or near-physiological dosages indicates that short-term therapy (up to three years) is not associated with an increased incidence of major cardiovascular events. These data are reassuring that there is not an early, large risk of testosterone, but longer-term follow-up of randomized controlled studies of testosterone therapy must be done. The majority of the evidence indicates that there is no increased risk of adverse major cardiovascular outcomes associated with testosterone therapy when administered at typical replacement dosages for hypogonadism.
6 The effects of endogenous and exogenous testosterone (and its major metabolites) on the risk of specific cardiovascular outcomes in men
There are five specific important cardiovascular disorders that have been studied in more detail than other cardiovascular outcomes that we will briefly review here: myocardial infarction, stroke, venous thromboembolism, heart failure, and atrial fibrillation.
6.1 Effects of endogenous and exogenous testosterone on the risk of myocardial infarction
In summary, the current data suggest that there is no association between serum endogenous testosterone concentrations or exogenous testosterone therapy and the risk of myocardial infarction. However, the current evidence is too weak to make a firm conclusion. It is likely that any beneficial or adverse effect of endogenous testosterone concentrations or testosterone replacement therapy on myocardial risk is small, and it will require very large numbers of men in randomized, controlled studies and carefully designed, large prospective cohort studies to determine if there is an effect [68].
6.2 The effects of endogenous and exogenous testosterone (and its major metabolites) on the risk of stroke
As with myocardial infarction, the current data suggest that testosterone replacement therapy for male hypogonadism (defined as symptoms and signs of testosterone deficiency, reproducibly low serum testosterone concentrations, and an identified disorder of the hypothalamus-pituitary axis) has no effect on the risk of stroke. B
6.3 The effects of endogenous and exogenous testosterone (and its major metabolites) on the risk of venous thromboembolic disease (deep venous thrombosis and/or pulmonary embolism)
In summary, based on several epidemiological studies and a small number of clinical trials that were generally short in duration (≤1 year) and potentially biased, the evidence suggests that testosterone replacement therapy does not increase the risk of idiopathic VTE. The evidence does not exclude the possibility that testosterone replacement therapy might increase the risk of VTE in men with underlying thrombophilia or that pharmacological dosage of testosterone (including men with baseline normal serum testosterone concentrations and no identified cause of hypogonadism) might increase the risk of VTE.
6.4 The effects of endogenous and exogenous testosterone on the risk of heart failure
Based on limited data, testosterone does not appear to have a major role in the pathogenesis, exacerbation, or treatment of heart failure, but low serum testosterone concentrations might be a marker of poor prognosis in men with heart failure.
6.5 The effects of endogenous and exogenous testosterone (and dihydrotestosterone) on the risk of atrial fibrillation
The current evidence precludes a firm conclusion about the role of testosterone in the pathophysiology and incidence of atrial fibrillation, but it seems unlikely that serum endogenous testosterone concentrations or testosterone replacement have a large effect on this common cardiac arrhythmia.
6.6 Summary of the effects of endogenous and exogenous T on specific cardiovascular outcomes: myocardial infarction, stroke, VTE, heart failure, or atrial fibrillation
Overall, the current evidence is reassuring that testosterone replacement therapy at typical dosages for bona fide male hypogonadism is unlikely to greatly increase the risk of myocardial infarction, stroke, VTE, heart failure, or atrial fibrillation (Fig. 2a). The available evidence is inconclusive to determine there might be small effects on the risk of these specific cardiovascular disorders. It is also possible that testosterone replacement therapy might increase cardiovascular risk in specific cohorts of men such as men with a recent myocardial infarction (<1 month prior) or men with recurrent idiopathic VTE. In those populations, the benefits and risks of testosterone replacement therapy must be carefully assessed.
7 High‑dosage testosterone use and androgenic steroid abuse
8 Exogenous estrogen trials and cardiovascular risk
9 Exogenous dihydrotestosterone trials and cardiovascular risk
10 Investigational male hormonal contraceptives and cardiovascular risk
11 Potential mechanisms of cardiovascular risk effects of testosterone and its metabolites
12 Future studies of testosterone therapy and cardiovascular risk
There are three broad groups of men that would most benefit from a more extensive study of the cardiovascular effects of testosterone therapy: hypogonadal males, middle-aged to older men with low serum testosterone concentrations and no identifiable disorder of the hypothalamus-pituitary–testicular axis, and eugonadal men taking pharmacological dosages of testosterone. For hypogonadal males, prospective case-control of studies boys and men with enrollment at the time of initiation of testosterone would be invaluable. These studies could be done in countries with regional or national health registries and could be funded by manufacturers of testosterone formulations. For middle-aged and older men with low serum testosterone concentrations and no identifiable disorder of the hypothalamus-pituitary–testicular axis, randomized, placebo-controlled studies are key. The United States TRAVERSE study is the first such study. It is a 5-year study of 5,246 men, ages 45–80 years old, at high risk of cardiovascular events and a serum total testosterone concentration<300 ng/dL (https://www.clinicaltrials gov/ct2/show/NCT0351803). The primary outcome is the time to the aggregate of nonfatal myocardial infarction, nonfatal stroke, cardiovascular revascularization, or cardiovascular death. Enrollment has been completed, and there has been no early discontinuation of the study—suggesting no clear safety signal. The initial results are expected to be announced in 2023. For eugonadal men using androgenic steroids, the most useful initial studies would be follow-up cohort studies using national registries; the use of randomized response questionnaire techniques and enrollment into a de-identified database that is linked to the cardiovascular risk factors and outcomes in a national health registry would ensure anonymity and greatly enhance recruitment and reliability of results.
13 Summary
Most of the data on the effects of endogenous and exogenous testosterone is derived from epidemiological studies (Fig. 1). The majority of the epidemiological studies demonstrate no association between serum concentrations of endogenous testosterone on major cardiovascular outcomes including overall mortality, cardiovascular deaths, myocardial infarction, stroke, and VTE, heart failure and atrial fibrillation. Some epidemiological studies demonstrate an inverse relationship between serum endogenous testosterone concentrations and major cardiovascular outcomes, but that inverse association is likely due to reverse causation.
Based on pharmacoepidemiological studies and a small number of randomized controlled studies that were not designed to assess cardiovascular outcomes, there is no adverse safety signal for major cardiovascular outcomes in men treated with testosterone therapy at typical replacement or near-replacement dosages.
14 Conclusions and clinical guidance
The past 50 years of research have clarified that testosterone and estradiol are not Manichean hormones: testosterone is not “bad for the human heart” nor is estradiol “good for the human heart”. Although epidemiological studies suggest a strong benefit of estrogen therapy for menopausal women, randomized controlled trials failed to confirm this benefit. Based on randomized, controlled trials of estrogen therapy with or without the addition of progestin, there is a small increased risk of major cardiovascular events in certain cohorts of women such as women over age 60 years initiating this hormone therapy year after menopause. However, younger women who initiate hormone therapy early on the onset of menopause might benefit or at least have little or no increased cardiovascular risk. There is no equivalent evidence base derived from randomized, placebo-controlled trials of testosterone therapy for men with low serum testosterone concentrations. However, as with menopausal women treated with estrogen therapy, the cardiovascular risk associated with testosterone therapy for hypogonadal men is likely to have a small effect. As women and estrogen, the cardiovascular risk is also likely to vary based on the age and underlying health (including the hypothalamus-pituitary–testicular axis function) of the man, the dosage of testosterone, and possibly the formulation of testosterone.
For clinicians and patients, the current evidence about the cardiovascular risk of testosterone therapy in men favors the following conclusions:
1. Testosterone therapy should not be initiated in men with low serum endogenous testosterone concentrations in order to reduce cardiovascular risk.
2. The benefits of testosterone therapy for improved quality of life, sexual function, increased muscle mass and strength, and bone health outweighs the potential cardiovascular safety concerns in most men with hypogonadism due to an identified disorder of the hypothalamus-pituitary-testicular axis. (Fig. 2a)
3. For men with borderline low-normal serum testosterone concentrations, the potential adverse cardiovascular effects of testosterone outweigh the unproven benefits of exogenous testosterone therapy (Fig. 2b).
4. Men who are initiated on testosterone therapy should be informed the United States Food and Drug Administration and Health Canada agencies have issued warnings about the possible increased risk of myocardial infarction, stroke, and venous thromboembolic disease with testosterone therapy, but the European Medicines Agency and Australian Therapeutic Goods Administration concluded there was no consistent evidence or a weak signal (respectively) for concerns about cardiovascular safety with testosterone therapy.
5. For hypogonadal men with hypogonadism due to an identified disorder of the hypothalamus-pituitary-testicular axis with a high risk of cardiovascular events (e.g., men with myocardial infarction in the past month or men with recurrent venothromboembolic events), the benefit-ratio should be considered before initiation of testosterone therapy and alternative therapies for specific conditions (e.g., bisphosphonates to increase bone density in men at higher risk of developing osteoporosis) should be considered.
*The current evidence for testosterone and incident risk of cardiovascular events is weak, but the evidence supports the conclusion that, at worst, any increase in absolute risk of adverse cardiovascular effects is likely to be small. However, that small possible risk is enough to discourage clinicians and patients to avoid promiscuous testosterone prescriptions without a strong rationale for such therapy.
Arthi Thirumalai · Bradley D. Anawalt
Abstract
In this narrative review, we discuss the evidence about the controversy about the cardiovascular effects of endogenous and exogenous testosterone in men. Prospective cohort studies with follow-ups of~5–15 years generally indicate no association or a possible inverse relationship between serum endogenous testosterone concentrations and composite major cardiovascular events, cardiovascular deaths, and overall mortality. Pharmacoepidemiological studies of large databases generally show no association between testosterone therapy and incident major cardiovascular events, and some pharmacoepidemiological studies demonstrate an association with decreased overall mortality. Randomized, placebo-controlled trials indicate that there is no increased incidence of overall major cardiovascular events with 1–3 years of testosterone therapy. These placebo-controlled trials have major limitations including small numbers of participants, short duration of testosterone therapy and follow-up, and lack of systematic adjudication of cardiovascular events. Overall, the evidence indicates that endogenous testosterone concentrations and testosterone therapy at physiological dosages confer no or minimal effects on the incidence of cardiovascular outcomes. There is insufficient evidence to make conclusions about testosterone therapy for patients at high risk of cardiovascular events (e.g., men with recent myocardial infarctions or stroke and men with recurrent idiopathic deep venous thromboses). In general, clinicians should avoid prescribing supraphysiological testosterone therapy to hypogonadal men or men with slightly low to low-normal serum testosterone concentrations and no identified disorder of the hypothalamus-pituitary-testicular axis because of the uncertain cardiovascular risks and the lack of proven health benefits. For most men with bona fide hypogonadism, the benefits of testosterone therapy exceed the potential risk of adverse cardiovascular effects.
Introduction
One of the raging controversies in the field of reproductive endocrinology is the role of sex hormones in the pathophysiology of cardiovascular disease and whether testosterone and estrogen increase or decrease the risk of cardiovascular events in humans. More is known about the effects of sex steroid hormones and cardiovascular risk in women than in men, and the lessons learned from randomized controlled trials in women are instructive to the nascent research and clinical care of men. It is important to understand the history of the anecdotal basis for the original simplistic hypotheses that “estrogen is good for the heart” and “testosterone is bad for the heart” for women and for men. The past three decades of women’s health research have demonstrated and reinforced two key concepts: 1) epidemiological studies are typically best suited for the development of hypotheses and require a randomized controlled trial for confirmation of these hypotheses; and 2) there are no simple conclusions about the effects of sex steroid hormones on cardiovascular risk: estrogen is not a cardiovascular panacea nor is testosterone a cardiovascular toxin. Although research on the effects of sex steroids on cardiovascular risk in men has lagged decades behind research on this topic in women, the same lessons seem to apply. We briefly review the poor evidence that stimulated the simplistic (and erroneous) polemical hypotheses that estrogen is beneficial and testosterone is detrimental to human cardiovascular health. We will also briefly review the key studies of the effects of sex steroid hormones on cardiovascular risk in women to provide context for the research of men that has been largely based on epidemiology studies.
In this narrative review, we summarize the findings of a large number of epidemiological studies and the scanty evidence from randomized clinical trials of the effects of testosterone and its major metabolites (estradiol and dihydrotestosterone) on cardiovascular outcomes in men (Fig. 1). This reviewed a search of PubMed from January 1, 2000, to March 1, 2022, and Google Scholar using the terms “testosterone and stroke”, “testosterone and myocardial infarction” “testosterone and cardiovascular disease”, “testosterone and deep venous thrombosis”, “testosterone and pulmonary embolism”, “hypogonadism and cardiovascular disease”, “hypogonadism and myocardial infarction”, and “hypogonadism and stroke”. In addition, we scanned the reference section of articles derived from the above search to retrieve additional salient articles.
In men, as with women, there is a distinction between the potential risks and benefits of naturally occurring endogenous concentrations of sex steroid hormone concentrations and testosterone therapy. There is also an important distinction between sex steroid hormone replacement therapy at physiological or near-physiological dosages in hypogonadal men and women (e.g., a premenopausal woman with gonadotropin deficiency due to a pituitary macroadenoma) versus sex steroid hormone therapy for a man without hypogonadism due to an identified disorder of the hypothalamus-pituitary-testicular axis or sex steroid hormone therapy for a postmenopausal woman. We use the cautionary lessons learned from sex hormone studies in women and the current evidence in men to make conclusions and clinical recommendations about testosterone therapy for male hypogonadism.
2 Serum sex steroid hormone concentrations and risk of cardiovascular events in women
2.1 Sex steroid hormone therapy and cardiovascular risk in postmenopausal women
In summary, there were early, biased observations by renowned clinicians that suggested that men are at a greatly higher risk of cardiovascular disease than women and led to the general hypotheses that estrogen is “good” for cardiovascular health and testosterone is “bad” for cardiovascular health. However, the most recent epidemiological data indicate that there are small differences in the overall incidence of cardiovascular disease between men and women and that these differences vary based on the specific cardiovascular disorder and the age cohort of the men and women [3]. In addition, the estrogen treatment trials of menopausal women have yielded complex results that belie a simple conclusion that estrogen is uniformly “good” or “bad” for postmenopausal women who have the highest risk of cardiovascular disease and cardiovascular death.
3 Endogenous serum sex steroid hormone concentrations and cardiovascular outcomes in men
3.1 Prospective immunoassay cohort studies of serum endogenous sex hormones and overall cardiovascular risk and mortality in men
3.2 Prospective mass spectrometry cohort studies of serum endogenous sex hormones and overall cardiovascular risk and mortality in men
3.3 Possible reverse causality between endogenous serum testosterone concentrations and overall cardiovascular risk and mortality in men
3.4 Summary of epidemiology of serum endogenous sex hormone concentrations and incident overall cardiovascular risk and mortality in men
The epidemiological data suggest that endogenous serum testosterone, DHT, and estradiol concentrations are not highly associated with future incident risk of overall cardiovascular events, cardiovascular mortality, or all-cause mortality. Although some studies show an inverse association between baseline serum concentrations of testosterone, DHT, and estradiol, with incident risk of major cardiovascular events and/or overall mortality, there is no consistent pattern among the prospective cohort studies. In addition, this inverse association might be due to reverse causality because older men with higher body mass indices or waist circumferences and multiple morbidities have lower serum testosterone concentrations and higher incident risk of major cardiovascular events and all-cause mortality.
4 Low serum testosterone due to therapeutic suppression in men: increased overall cardiovascular risk and mortality?
Although androgen deprivation therapy for the treatment of prostate cancer is associated with metabolic syndrome, adverse effects of body composition, and increased incident risk of myocardial infarction and venothromboembolic events, the causal relationship has not been proven [40, 41]. An equally plausible hypothesis is that men with more advanced prostate cancer that is treated with androgen deprivation therapy tend to have worse general health and a higher risk of major cardiovascular outcomes than the control comparator groups in the published epidemiological studies [40].
5 Testosterone therapy and overall cardiovascular risk and mortality in men
In summary, the data from pharmaco-epidemiological studies are mixed, but the majority of the studies demonstrate no association between testosterone therapy and incident risk of major cardiovascular events. The limited data from modest-sized randomized clinical trials for testosterone replacement therapy at typical physiological or near-physiological dosages indicates that short-term therapy (up to three years) is not associated with an increased incidence of major cardiovascular events. These data are reassuring that there is not an early, large risk of testosterone, but longer-term follow-up of randomized controlled studies of testosterone therapy must be done. The majority of the evidence indicates that there is no increased risk of adverse major cardiovascular outcomes associated with testosterone therapy when administered at typical replacement dosages for hypogonadism.
6 The effects of endogenous and exogenous testosterone (and its major metabolites) on the risk of specific cardiovascular outcomes in men
There are five specific important cardiovascular disorders that have been studied in more detail than other cardiovascular outcomes that we will briefly review here: myocardial infarction, stroke, venous thromboembolism, heart failure, and atrial fibrillation.
6.1 Effects of endogenous and exogenous testosterone on the risk of myocardial infarction
In summary, the current data suggest that there is no association between serum endogenous testosterone concentrations or exogenous testosterone therapy and the risk of myocardial infarction. However, the current evidence is too weak to make a firm conclusion. It is likely that any beneficial or adverse effect of endogenous testosterone concentrations or testosterone replacement therapy on myocardial risk is small, and it will require very large numbers of men in randomized, controlled studies and carefully designed, large prospective cohort studies to determine if there is an effect [68].
6.2 The effects of endogenous and exogenous testosterone (and its major metabolites) on the risk of stroke
As with myocardial infarction, the current data suggest that testosterone replacement therapy for male hypogonadism (defined as symptoms and signs of testosterone deficiency, reproducibly low serum testosterone concentrations, and an identified disorder of the hypothalamus-pituitary axis) has no effect on the risk of stroke. B
6.3 The effects of endogenous and exogenous testosterone (and its major metabolites) on the risk of venous thromboembolic disease (deep venous thrombosis and/or pulmonary embolism)
In summary, based on several epidemiological studies and a small number of clinical trials that were generally short in duration (≤1 year) and potentially biased, the evidence suggests that testosterone replacement therapy does not increase the risk of idiopathic VTE. The evidence does not exclude the possibility that testosterone replacement therapy might increase the risk of VTE in men with underlying thrombophilia or that pharmacological dosage of testosterone (including men with baseline normal serum testosterone concentrations and no identified cause of hypogonadism) might increase the risk of VTE.
6.4 The effects of endogenous and exogenous testosterone on the risk of heart failure
Based on limited data, testosterone does not appear to have a major role in the pathogenesis, exacerbation, or treatment of heart failure, but low serum testosterone concentrations might be a marker of poor prognosis in men with heart failure.
6.5 The effects of endogenous and exogenous testosterone (and dihydrotestosterone) on the risk of atrial fibrillation
The current evidence precludes a firm conclusion about the role of testosterone in the pathophysiology and incidence of atrial fibrillation, but it seems unlikely that serum endogenous testosterone concentrations or testosterone replacement have a large effect on this common cardiac arrhythmia.
6.6 Summary of the effects of endogenous and exogenous T on specific cardiovascular outcomes: myocardial infarction, stroke, VTE, heart failure, or atrial fibrillation
Overall, the current evidence is reassuring that testosterone replacement therapy at typical dosages for bona fide male hypogonadism is unlikely to greatly increase the risk of myocardial infarction, stroke, VTE, heart failure, or atrial fibrillation (Fig. 2a). The available evidence is inconclusive to determine there might be small effects on the risk of these specific cardiovascular disorders. It is also possible that testosterone replacement therapy might increase cardiovascular risk in specific cohorts of men such as men with a recent myocardial infarction (<1 month prior) or men with recurrent idiopathic VTE. In those populations, the benefits and risks of testosterone replacement therapy must be carefully assessed.
7 High‑dosage testosterone use and androgenic steroid abuse
8 Exogenous estrogen trials and cardiovascular risk
9 Exogenous dihydrotestosterone trials and cardiovascular risk
10 Investigational male hormonal contraceptives and cardiovascular risk
11 Potential mechanisms of cardiovascular risk effects of testosterone and its metabolites
12 Future studies of testosterone therapy and cardiovascular risk
There are three broad groups of men that would most benefit from a more extensive study of the cardiovascular effects of testosterone therapy: hypogonadal males, middle-aged to older men with low serum testosterone concentrations and no identifiable disorder of the hypothalamus-pituitary–testicular axis, and eugonadal men taking pharmacological dosages of testosterone. For hypogonadal males, prospective case-control of studies boys and men with enrollment at the time of initiation of testosterone would be invaluable. These studies could be done in countries with regional or national health registries and could be funded by manufacturers of testosterone formulations. For middle-aged and older men with low serum testosterone concentrations and no identifiable disorder of the hypothalamus-pituitary–testicular axis, randomized, placebo-controlled studies are key. The United States TRAVERSE study is the first such study. It is a 5-year study of 5,246 men, ages 45–80 years old, at high risk of cardiovascular events and a serum total testosterone concentration<300 ng/dL (https://www.clinicaltrials gov/ct2/show/NCT0351803). The primary outcome is the time to the aggregate of nonfatal myocardial infarction, nonfatal stroke, cardiovascular revascularization, or cardiovascular death. Enrollment has been completed, and there has been no early discontinuation of the study—suggesting no clear safety signal. The initial results are expected to be announced in 2023. For eugonadal men using androgenic steroids, the most useful initial studies would be follow-up cohort studies using national registries; the use of randomized response questionnaire techniques and enrollment into a de-identified database that is linked to the cardiovascular risk factors and outcomes in a national health registry would ensure anonymity and greatly enhance recruitment and reliability of results.
13 Summary
Most of the data on the effects of endogenous and exogenous testosterone is derived from epidemiological studies (Fig. 1). The majority of the epidemiological studies demonstrate no association between serum concentrations of endogenous testosterone on major cardiovascular outcomes including overall mortality, cardiovascular deaths, myocardial infarction, stroke, and VTE, heart failure and atrial fibrillation. Some epidemiological studies demonstrate an inverse relationship between serum endogenous testosterone concentrations and major cardiovascular outcomes, but that inverse association is likely due to reverse causation.
Based on pharmacoepidemiological studies and a small number of randomized controlled studies that were not designed to assess cardiovascular outcomes, there is no adverse safety signal for major cardiovascular outcomes in men treated with testosterone therapy at typical replacement or near-replacement dosages.
14 Conclusions and clinical guidance
The past 50 years of research have clarified that testosterone and estradiol are not Manichean hormones: testosterone is not “bad for the human heart” nor is estradiol “good for the human heart”. Although epidemiological studies suggest a strong benefit of estrogen therapy for menopausal women, randomized controlled trials failed to confirm this benefit. Based on randomized, controlled trials of estrogen therapy with or without the addition of progestin, there is a small increased risk of major cardiovascular events in certain cohorts of women such as women over age 60 years initiating this hormone therapy year after menopause. However, younger women who initiate hormone therapy early on the onset of menopause might benefit or at least have little or no increased cardiovascular risk. There is no equivalent evidence base derived from randomized, placebo-controlled trials of testosterone therapy for men with low serum testosterone concentrations. However, as with menopausal women treated with estrogen therapy, the cardiovascular risk associated with testosterone therapy for hypogonadal men is likely to have a small effect. As women and estrogen, the cardiovascular risk is also likely to vary based on the age and underlying health (including the hypothalamus-pituitary–testicular axis function) of the man, the dosage of testosterone, and possibly the formulation of testosterone.
For clinicians and patients, the current evidence about the cardiovascular risk of testosterone therapy in men favors the following conclusions:
1. Testosterone therapy should not be initiated in men with low serum endogenous testosterone concentrations in order to reduce cardiovascular risk.
2. The benefits of testosterone therapy for improved quality of life, sexual function, increased muscle mass and strength, and bone health outweighs the potential cardiovascular safety concerns in most men with hypogonadism due to an identified disorder of the hypothalamus-pituitary-testicular axis. (Fig. 2a)
3. For men with borderline low-normal serum testosterone concentrations, the potential adverse cardiovascular effects of testosterone outweigh the unproven benefits of exogenous testosterone therapy (Fig. 2b).
4. Men who are initiated on testosterone therapy should be informed the United States Food and Drug Administration and Health Canada agencies have issued warnings about the possible increased risk of myocardial infarction, stroke, and venous thromboembolic disease with testosterone therapy, but the European Medicines Agency and Australian Therapeutic Goods Administration concluded there was no consistent evidence or a weak signal (respectively) for concerns about cardiovascular safety with testosterone therapy.
5. For hypogonadal men with hypogonadism due to an identified disorder of the hypothalamus-pituitary-testicular axis with a high risk of cardiovascular events (e.g., men with myocardial infarction in the past month or men with recurrent venothromboembolic events), the benefit-ratio should be considered before initiation of testosterone therapy and alternative therapies for specific conditions (e.g., bisphosphonates to increase bone density in men at higher risk of developing osteoporosis) should be considered.
*The current evidence for testosterone and incident risk of cardiovascular events is weak, but the evidence supports the conclusion that, at worst, any increase in absolute risk of adverse cardiovascular effects is likely to be small. However, that small possible risk is enough to discourage clinicians and patients to avoid promiscuous testosterone prescriptions without a strong rationale for such therapy.
