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Testosterone replacement and cardiovascular disease risk: what do endocrinologists need to know?

Gonzalez, Joshua R.; Goldstein, Irwin

Cardiovascular Endocrinology & Metabolism: September 2015 - Volume 4 - Issue 3 - p 100–107
doi: 10.1097/XCE.0000000000000051
Invited reviews
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Testosterone deficiency (or hypogonadism) affects millions of men worldwide. Consensus regarding an appropriate biochemical cutoff for the definition and treatment of hypogonadism has been challenging. Several recent, well-publicized studies have called into question the long recognized benefits of testosterone replacement therapy. The aim of the current article is to review the data on testosterone treatment, paying specific attention to the potential cardiovascular effects of this increasingly common therapy. We examine some of the most common cardiovascular diseases including hypertension, metabolic syndrome, coronary artery disease, atherosclerosis, congestive heart failure, myocardial infarction, and stroke. This review will also investigate the potential effect of testosterone replacement therapy on cardiovascular and all-cause mortality and address a growing fear among the medical community about the safety of testosterone replacement.

San Diego Sexual Medicine, Alvarado Hospital, San Diego, California, USA

Correspondence to Irwin Goldstein, MD, San Diego Sexual Medicine, Alvarado Hospital, 5555 Reservoir Drive, Suite 300, San Diego, CA 92120, USA Tel: +1 619 265 8865; fax: +1 619 265 7696; e-mail: dr.irwingoldstein@gmail.com

Received November 24, 2014

Accepted February 25, 2015

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Introduction

Testosterone deficiency (or hypogonadism) – a condition based on signs and symptoms of biochemically confirmed low testosterone (T) – affects up to 30% of the adult general male population, which translates into millions of men worldwide 1–4. Testosterone is known to decrease progressively and linearly with age. With increases in the aging population, the number of men with hypogonadal symptoms worldwide is expected to nearly double in the next decade 2. There has been an increase in testosterone prescriptions written over the last decade for hypogonadal men and the pharmaceutical industry has responded with new options for hypogonadal treatment. The exponential growth of this industry has caused skepticism in some medical professionals 4,5.

Defining what constitutes significantly low testosterone remains a large problem facing clinicians. Biochemical parameters dictating hypogonadism have been set at a variety of cutoffs. The Food and Drug Administration regularly uses a minimum value of 300 ng/dl to define hypogonadism. Alternative definitions have been proposed by others including a consensus statement from the International Society of Andrology (ISA), the International Society for the Study of the Aging Male (ISSAM), the European Association of Urology (EAU), the European Association of Andrology (EAA), and the American Society of Andrology (ASA). Although there is no globally agreed upon serum level that warrants intervention, these societies suggest that a testosterone below 230 ng/dl along with clinical symptoms of hypogonadism would likely benefit from therapy 6. The inability of professional groups to agree on a unifying biochemical parameter has left many clinicians confused as to when they should initiate testosterone replacement. Further complicating the matter is the lack of standardization of testosterone measurement, with the medical community relying instead on a variety of laboratory assays with different ranges of normal 7,8. Finally, there are downstream biological phenomena, such as genetic differences in androgen receptor structure, 5 α-reductase activity, and levels of both sex hormone binding globulin and unbound, free testosterone – all of which may impact on the presence or severity of hypogonadal symptoms.

Testosterone deficiency has been shown to be more common in men with a number of serious medical conditions including obesity, diabetes, hypertension, hyperlipidemia, depression, osteoporosis, chronic obstructive pulmonary disease, and lower urinary tract symptoms or benign prostatic hypertrophy 9,10. One review of 53 studies published in the last decade also suggested that low testosterone might be associated with negative health consequences 11. Among the male veteran population, low serum testosterone has been associated with increased mortality 12. Alternatively, testosterone replacement therapy (TRT) has demonstrated improvements in mood, sexual function and libido, lipid levels, glycemic control, muscle mass and strength 13–15.

Despite these improvements and the well-recognized consequences of testosterone deficiency, many healthcare providers remain wary of recommending TRT for patients with hypogonadism 16. This hesitation was recently amplified with the publication of several studies reporting increased cardiovascular events and mortality with the use of testosterone 17,18. In a meta-analysis of placebo-controlled randomized trials, Xu et al.19 reported that exogenous testosterone therapy increased the risk of cardiovascular-related events. These data contradict other published work, which has demonstrated a statistically significant relationship between low testosterone levels and adverse negative cardiovascular events, lower cardiovascular risk in elderly men with higher testosterone values, and reduced mortality in hypogonadal men on testosterone therapy 12,20,21.

However, for some, the correlation between testosterone therapy and cardiovascular risk remains ambiguous. To address a growing fear in the medical community about the use of testosterone therapy, we performed a review of the available literature. The objective of the current review is to summarize the data on testosterone treatment, paying specific attention to the potential cardiovascular effects of this increasingly common therapy.

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Hypertension and metabolic syndrome

Men have higher blood pressure than do women for most of their lives 22. The difference in blood pressure is often a presumed consequence of higher levels of circulating testosterone in men, yet the opposite has been demonstrated. Low serum testosterone levels in men have been associated with increased risk of hypertension in a number of studies 23,24. Mulligan et al.10 found a significant difference in reported hypertension between eugonadal and hypogonadal men, with a higher proportion of hypogonadal patients reporting not only a history of hypertension, but also hyperlipidemia, diabetes, and obesity. In a meta-analysis of more than 30 randomized clinical trials, Corona et al. 25 found that administration of testosterone actually ameliorated blood pressure, in addition to being significantly associated with a reduction of fat mass and hemoglobin A1c. Testosterone treatment was generally well tolerated in the studies reviewed and was not associated with risk of cardiovascular disease.

The concern over testosterone’s relationship to blood pressure exists primarily because of data collected from animal models. Testosterone is known to cause water and sodium retention, possibly through activation of the renin–angiotensin system or by direct effect on tubular reabsorption of sodium through the androgen receptor 26,27. The increased proximal tubule reabsorption caused by upregulation of renin–angiotensin system has been linked to significant increases in blood pressure in rats 27,28. In addition, others have demonstrated in animal models that testosterone may promote renal injury and lead to decline in renal function 28–30. However, an increase in blood pressure and subsequent renal damage has not been reliably demonstrated in clinical studies.

Although the increased risk of hypertension has been well documented in men abusing anabolic steroids, the same has not been proven in men on TRT who achieve normal physiologic levels 31,32. More than 20 years ago, Mårin et al.33 reported that the administration of transdermal T to obese men significantly reduced diastolic blood pressure. Similarly, another study found that administration of intramuscular T to men with osteoporosis was correlated with significant reductions in both systolic and diastolic blood pressure 34. Lastly, a more recent study out of Germany demonstrated that TRT in hypogonadal men resulted in a significant reduction in both resting systolic and diastolic blood pressure 35.

The effect of testosterone on blood pressure has been studied most extensively in relation to the metabolic syndrome. The metabolic syndrome is characterized by central obesity, lipid and insulin dysregulation, and hypertension, and is considered a risk factor for the development of cardiovascular disease. Using data from the Massachusetts Male Aging Study, Kupelian et al. 36 concluded that low total T and clinical androgen deficiency were associated with increased risk of developing metabolic syndrome, even in nonobese men. This held true across racial and ethnic groups in a dose–response manner 37. Others have demonstrated a similar protective effect of endogenous androgens against obesity, diabetes, and metabolic syndrome 38,39. These studies corroborate the findings of increased risk of cardiovascular disease and diabetes seen previously in prostate cancer patients undergoing androgen deprivation therapy 40. As such, some have postulated that testosterone may be one of the most valuable markers of male body composition and overall health available to clinicians 41.

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Coronary artery disease and atherosclerosis

As with hypertension, testosterone is often blamed for the increased incidence of, and resulting mortality from, coronary artery disease (CAD) in men. Yet coronary atherosclerosis increases with age despite the marked decline in serum testosterone that occurs normally as men get older. Studies have demonstrated that men with clinically significant CAD actually have lower levels of bioavailable testosterone than appropriately matched controls 42. There is also growing evidence that testosterone levels are closely correlated with antiatherosclerotic markers. Clinically significant CAD has been associated with lower T and higher levels of interleukin-1β (IL-1β) and IL-10, both inflammatory cytokines implicated in the pathogenesis of CAD 43.

Atherosclerosis is an inflammatory process consisting of a delicate interplay between proinflammatory and anti-inflammatory cellular products and the formation of resulting plaques involves many predisposing factors 44. The early stages are marked by endothelial dysfunction, lipid deposition, and a local inflammatory response 45. In animal models, testosterone is protective against atherosclerosis and physiologic TRT has been shown to inhibit fatty streak formation, a known precursor to atheroma 46,47. Similar protective effects have been seen in clinical studies. Testosterone has been shown previously to act as an immunomodulator in a variety of disease states, including diabetes and CAD 48,49. Moreover, TRT has been associated with decreases in proinflammatory markers such as the aforementioned IL-1β, a suspected participant in the development of atherosclerosis. Serum levels of endothelin-1, a vasoconstrictive hormone involved in cardiovascular disease, are also higher in hypogonadal men, but can be corrected with TRT 50.

The negative relationship between low T and CAD has been recognized for some time. In a study from the early 1990s, testosterone was negatively correlated with prothrombotic factors such as fibrinogen and plasminogen activator inhibitor-1 and positively correlated with high-density lipoprotein (good) cholesterol 51. Another surrogate marker of atherosclerotic disease is carotid intima–media thickness, as measured by Doppler sonography. In one study, men with T in the lowest tertile had elevated carotid intima–media thickness and greater disease progression than men with higher testosterone levels 52. In addition, the Rotterdam Study found an independent inverse association between levels of total and bioavailable T and aortic atherosclerosis in men over the age of 55 53. Taken together, these studies strengthen the hypothesis that low T is not only linked to the formation of atherosclerosis and development of CAD, but also may accelerate progression of the disease.

In stark contrast to all the evidence presented thus far, a recently well-publicized study found that the use of testosterone therapy was associated with increased risk of adverse cardiovascular outcomes 18. Among hypogonadal men (T<300 ng/dl), Vigen and colleagues reported an increased rate of myocardial infarction (MI), stroke, and death in those who received a testosterone prescription compared with those who did not. The overall event curves revealed a significant increase of 29% in adverse events for testosterone-prescribed men. However, the raw data demonstrated the opposite effect: namely, the percentage of men who actually suffered an event was more than double in the non-T group versus those prescribed testosterone (10.1 vs. 21.2%) 54. This inconsistency suggests that the study conclusions are largely the result of complex statistical modeling and do not represent any real increased cardiovascular risk of T therapy. In addition, the authors inappropriately excluded more than 1100 men who suffered stroke or MI before receiving a prescription. If these men had been included, the rate of events in the non-T group would have increased by more than 70%, thereby reversing the authors’ claims 55. The authors also did not account for when prescriptions were filled, resulting in a non-T group composed of both men on and off treatment. Finally, men in this study on T therapy were insufficiently treated and would still be considered hypogonadal by many expert groups (mean follow-up T=332 ng/dl). Despite all of the inherent flaws and the plethora of evidence to the contrary, the authors still concluded that testosterone therapy was potentially responsible for these adverse cardiac events.

Finally, Xu et al.19 recently published a meta-analysis of placebo-controlled randomized trials of testosterone therapy. The authors concluded based on the available literature that testosterone therapy increased cardiovascular-related events. They point out that among trials funded by the pharmaceutical industry testosterone had no effect on cardiovascular-related events, but in those with alternate sources of funding testosterone substantially increased the risk. However, Xu and colleagues identify some considerable limitations to their work. First, not all testosterone trials report all cardiovascular-related events. Some men included in the meta-analysis also stopped treatment because of increased prostate-specific antigen or polycythemia, which could result in bias towards the null. The authors also recognize that meta-analysis are less reliable than large randomized controlled trials, some of which have demonstrated disparate results 56–58.

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Congestive heart failure

Congestive heart failure (CHF) is a common complication of longstanding cardiovascular disease associated with considerable morbidity and an annual mortality rate up to 30% 59. TRT has been traditionally withheld from men with a history of CHF because of the concern over potential increased fluid retention that can occur while on treatment. However, testosterone deficiency is an independent marker of poor prognosis and survival for men with heart failure, indicating that these men would likely benefit from TRT 60.

The benefits of testosterone in patients with CHF are only beginning to be appreciated. TRT helps to decrease circulating levels of inflammatory mediators like IL-1β and tumor necrosis factor-α, both implicated in heart failure 49. Pugh et al. 61 found that buccal testosterone acutely improved cardiac output and systemic vascular resistance, with no other adverse effects on hemodynamic parameters. More lasting effects have also been seen. In a double blind randomized clinical trial, testosterone was shown to improve functional capacity and symptoms in men with moderately severe heart failure 58. Malkin et al. 62 also demonstrated an improvement in fasting insulin sensitivity in men with CHF treated with testosterone. Most importantly, treatment was well tolerated and no adverse effects – including increased fluid retention – were seen. Another double blind, placebo-controlled, randomized study demonstrated that long-acting testosterone improved peak oxygen consumption, exercise capacity, muscle strength, and glucose metabolism in men with moderately severe CHF 63. All of these data provide supportive evidence to dismiss fears about the use of TRT in men with CHF 64. Given the excessive morbidity and mortality of CHF, men with this condition stand to benefit tremendously from testosterone therapy for its effect on both quality of life and symptom improvement.

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Myocardial infarction and stroke

MI and stroke represent two particularly concerning events for clinicians, which has led to fear over the safety of TRT in men at risk for these diseases. However, there are no good data to support this hesitation. In a recently published large, retrospective cohort study, Baillargeon et al.65 found that older men treated with intramuscular testosterone were not at increased risk for MI. Furthermore, testosterone use was modestly protective against MI for men with high risk. The Health in Men Study – a population-based cohort study of Australian men – demonstrated that higher plasma levels of both testosterone and dihydrotestosterone (DHT) were biomarkers for reduced risk of stroke 66. In another study, higher total T was associated with a lower incidence of cardiovascular events including MI, transient ischemic attacks, and stroke in older men with and without prevalent cardiovascular disease 21.

The recently publicized results of The Testosterone in Older Men with Mobility Limitations (TOM) trial have left many uncertain about the safety of testosterone use in men at risk for MI. The trial was established to investigate the safety and efficacy of testosterone treatment in older men with limitations in mobility 17. The study was stopped early because of an increase in reported adverse cardiovascular events among men being treated with testosterone, but was never designed to specifically assess cardiovascular risk. Four major cardiac events – one death, two MIs, and one stroke – occurred in 209 men with substantial comorbidities over a 6-month period 54.

The results of the TOM trial must be looked at cautiously, especially because they differ significantly from previous clinical trial of TRT 67. Most notably, the TOM trial was not adequately powered to assess cardiovascular events. The events recorded also included a wide range of symptoms and sequelae, some of unclear clinical significance. Second, the TOM trial population was comprised of frail, elderly men (mean age=74 years) with multiple comorbidities who were at baseline already at risk of adverse cardiovascular events. Third, the testosterone gel dosing in the study was problematic and excessive. Men in the TOM trial were started at 100 mg/day, more than twice the recommended dose used in clinical practice. Most notably, the conclusions drawn from this trial directly contradict earlier work by the same author, which demonstrated an increased risk of cardiovascular disease among men receiving long-term androgen deprivation therapy 68.

Apart from the TOM trial, no other major randomized double blind, placebo-controlled studies have reported adverse cardiovascular outcomes with TRT 67. In a similarly conducted study in the UK, Srinivas-Shankar et al.69 found exactly the opposite. Frail, elderly men in that study were treated appropriately with 50 mg daily testosterone gel or placebo. The authors reported a significant increase in lean body mass and decrease in fat mass among men on TRT. Interestingly, the only MI and death recorded occurred in the placebo group.

Finkle et al.70 found a two-fold to three-fold increased risk of nonfatal MI within the 90 days following an initial testosterone prescription among younger men with a history of heart disease. A similar two-fold risk was found among older men, regardless of cardiovascular risk history. However, the authors admit that relatively small numbers of MI cases occurred in each subgroup. This study was also retrospective in nature and based its conclusions on filled testosterone prescriptions, but offered no data on actual testosterone use. Similar concerns have been raised about the Vigen study 54,55. The authors here simply assumed that filling a prescription was an adequate surrogate for prescription use. The study does not control for type nor amount of testosterone prescribed; there is also no data on serum testosterone levels of men on treatment. Given these limitations, it is hard to conclude from the Finkle data that testosterone leads to a real increased risk of MI.

When kept within normal physiologic range, testosterone has proven safe in both healthy patients and those with cardiovascular risk. A recent French study of more than 3500 elderly men found a J-shaped association between testosterone and ischemic arterial disease, including stroke and coronary heart disease. The authors concluded that both high and low T is associated with increased risk of arterial ischemic events, but that optimal ranges of testosterone may actually confer protection against cardiovascular events 71. This may explain the aberrant outcomes reported in the TOM trial, whereby men were treated with abnormally high doses of testosterone.

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Cardiovascular and all-cause mortality

Maintaining testosterone in an optimal range is not only beneficial for cardiovascular health but also for overall mortality. Older men with midrange levels of T and DHT have been shown to have the lowest death rates from any cause 72. Furthermore, higher levels of DHT were associated with lower mortality from ischemic heart disease. A recent meta-analysis also found that low endogenous T was associated with an increased risk of both all-cause and cardiovascular mortality 73. These data echo findings from another meta-analysis, which demonstrated a correlation between low T and increased risk of cardiovascular mortality 74.

Data from population-based studies have shown similar results. In a study of US veterans, men with low and equivocal testosterone had higher mortality rates than men with normal levels after adjusting for age, medical comorbidities, BMI, and other potential clinical covariates 12. A prospective study that followed participants for more than 10 years found that men with total T levels in the lowest quartile were 40% more likely to die than those with higher levels. This association remained significant after adjusting for age, adiposity, lifestyle, and other clinical factors such as metabolic syndrome, diabetes, and prevalent cardiovascular disease 75. Another large study of Australian men similarly concluded that low T predicts cardiovascular mortality 76.

Three notable studies have failed to show a correlation between testosterone and mortality. First, the Massachusetts Male Aging Study (MMAS) followed a group of younger men (aged 40–70) for more than 15 years 77. In their multivariate model, higher free T and lowered DHT were significantly associated with ischemic heart disease mortality. However, the authors point out that there was no correlation with total testosterone nor sex hormone-binding globulin and that the free T and DHT association with ischemic heart disease mortality could be due to chance. The Caerphilly study, another prospective cohort study of younger men (aged 45–59), also found no association between total T and all-cause mortality 78. Both of these studies included younger men, which may explain the difference between their results and other aforementioned studies 67. Lastly, the Framingham Heart Study – a prospectively evaluated cohort of elderly men (mean age 75 years) – found no association between baseline hormone concentrations and their trajectories with incident cardiovascular disease and all-cause mortality 79. Still, the authors admit that the advanced age and small size of their cohort, competing cardiovascular and mortality risk, and limited statistical power may explain the lack of association in their study.

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Conclusion

An overwhelming majority of the available literature indicates that low testosterone is a predictor of increased cardiovascular events and even death (Table 1). When used in correct doses, testosterone is safe in patients both at risk of and with a history of cardiovascular disease. The persistent fear among the medical community regarding the safety of TRT is largely the result of well publicized, but poorly designed studies or data extrapolated from animal models. This fear exists despite evidence to support the contrary: namely, testosterone deficiency can lead to a variety of adverse events and even promote progression of pre-existing cardiovascular disease.

Table 1

Table 1

Hypogonadism is associated with poorer quality of life, reduced activity and strength, fatigue, mood alteration, and cognitive difficulties 67. All of these factors in addition to the known cardiovascular consequences of low T could potentially contribute to earlier mortality, making testosterone an important marker of overall health.

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Acknowledgements

Conflicts of interest

Irwin Goldstein is an advisor/consultant for Allergan, Auxilium, Coloplast, Pfizer, Strategic Science & Technologies, TesoRx; a speaker for Pfizer; and a researcher for Allergan, Auxilium, Evidera, Lipocine, Medtronic Vascular, TesoRx, TGI, Vivus. Joshua R. Gonzalez has no conflicts of interest.

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Keywords:

cardiovascular risk; hypogonadism; testosterone replacement therapy

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