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Testosterone and the Cardiovascular System: A Comprehensive Review of the Clinical Literature

2013; Wiley; Volume: 2; Issue: 6 Linguagem: Inglês

10.1161/jaha.113.000272

2047-9980

Peyman Mesbah Oskui, William J. French, Michael J. Herring, Guy S. Mayeda, Steven Burstein, Robert A. Kloner,

Pharmacological Effects and Assays

HomeJournal of the American Heart AssociationVol. 2, No. 6Testosterone and the Cardiovascular System: A Comprehensive Review of the Clinical Literature Open AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citations ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toOpen AccessReview ArticlePDF/EPUBTestosterone and the Cardiovascular System: A Comprehensive Review of the Clinical Literature Peyman Mesbah Oskui, MD, William J. French, MD, Michael J. Herring, BS, Guy S. Mayeda, MD, Steven Burstein, MD and Robert A. Kloner, MD, PhD Peyman Mesbah OskuiPeyman Mesbah Oskui Department of Cardiology, Harbor‐UCLA Medical Center, Torrance, CA Heart Institute, Good Samaritan Hospital, Los Angeles, CA , William J. FrenchWilliam J. French Department of Cardiology, Harbor‐UCLA Medical Center, Torrance, CA , Michael J. HerringMichael J. Herring Heart Institute, Good Samaritan Hospital, Los Angeles, CA , Guy S. MayedaGuy S. Mayeda Department of Cardiology, Harbor‐UCLA Medical Center, Torrance, CA Heart Institute, Good Samaritan Hospital, Los Angeles, CA Department of Cardiology, Cedars‐Sinai Medical Center, Los Angeles, CA , Steven BursteinSteven Burstein Heart Institute, Good Samaritan Hospital, Los Angeles, CA Department of Cardiology, Cedars‐Sinai Medical Center, Los Angeles, CA and Robert A. KlonerRobert A. Kloner Heart Institute, Good Samaritan Hospital, Los Angeles, CA Department of Cardiology, Keck School of Medicine at the University of Southern California, Los Angeles, CA Originally published15 Nov 2013https://doi.org/10.1161/JAHA.113.000272Journal of the American Heart Association. 2013;2:e000272IntroductionRecent data from the Massachusetts Male Aging Study (MMAS) have revealed an increasing incidence of hypogonadism within the aging US population. The Massachusetts Male Aging Study estimates indicate that ≈2.4 million men aged 40 to 69 suffer from hypogonadism in the United States.1 The Massachusetts Male Aging Study also projects ≈481 000 new cases of hypogonadism annually in US men within the same age group.1 The true incidence of hypogonadism among US men may be in excess of the Massachusetts Male Aging Study estimates, given the stringent criteria that were used by the authors to define hypogonadism. Testosterone in men reaches maximum levels at approximately age 30, after which levels steadily decline at a rate of 1% to 2% annually.1 Controversy exists regarding whether the decline in testosterone with increasing age is a normal physiologic process or whether it is a result of chronic comorbidities and lifestyle choices. Testosterone levels are lower in patients with chronic illnesses such as end‐stage renal disease, human immunodeficiency virus, chronic obstructive pulmonary disease, type 2 diabetes mellitus (T2DM), obesity, and several genetic conditions such as Klinefelter syndrome.2, 3 Trauma, castration, radiation or chemotherapy, acute illness, and pituitary tumors are also known causes of hypotestosteronemia.2, 4 It is unknown whether low testosterone in patients who are ill is the cause of their illness or whether it is caused by their disease. The exact mechanism of action that leads to lower testosterone levels with age has not been discovered. New evidence from rat models suggests that the synthesis of testosterone by testicular Leydig cells in response to luteinizing hormone may decrease with age. Reactive oxygen species (ROS), which are generated by the mitochondria of Leydig cells, are a normal byproduct of testosterone synthesis. The accumulation of ROS over time may cause damage to the Leydig cell DNA and thereby render it incapable of producing testosterone.5The past 2 decades have witnessed a significant increase in the number of prescriptions for testosterone replacement therapy. Estimates suggest that since 1993 prescriptions for testosterone, regardless of the formulation, have increased nearly 500%.6 Reasons behind this dramatic increase in testosterone use include increased prevalence of physiologic testosterone deficiency secondary to the aging population, increased media attention to testosterone replacement therapy aimed at men and women, and the development and consequent wide marketing of new testosterone formulations, including transdermal testosterone. The recent flurry of direct consumer advertising of testosterone products on television and in print is difficult to ignore. On the other hand, the relationship between circulating testosterone and various aspects of cardiovascular health is not clearly understood. Furthermore, the effects of testosterone replacement therapy on risk factors of cardiovascular disease and major adverse cardiovascular outcomes are a point of contention.The goal of this article is to provide a comprehensive review of the clinical literature that has examined the associations between testosterone and cardiovascular disease including incidence of coronary artery disease, severity of coronary artery disease, mortality secondary to cardiovascular disease, angina pectoris, vasomotor regulation of coronary arteries, congestive heart failure, and QT interval prolongation. We also summarize findings from the clinical literature on the association of testosterone with risk factors of atherosclerosis including T2DM, dyslipidemia, obesity, and biomarkers of inflammation. Finally, we summarize the effects of testosterone replacement therapy on cardiovascular disease and its risk factors and major adverse cardiovascular events. When analyzing the content of this review article, it is important to note that a certain degree of between‐study heterogeneity is unavoidable because of the very large number of available studies. For instance, obesity is an important factor that must be considered when analyzing testosterone studies. Although most studies account for obesity in their analysis, others do not. Similar consideration should be given to the effects of obesity and insulin resistance on sex hormone–binding globulin (SHBG).Levels of Endogenous Testosterone in Men With Coronary Artery DiseaseHypogonadism is not considered a traditional risk factor for coronary artery disease (CAD). However, it is widely accepted that men experience a gradual decline in their testosterone levels with increasing age,7, 8, 9, 10, 11, 12 and male sex has long been considered a strong risk factor for CAD. Together, these 2 facts have prompted numerous investigators to search for a possible relationship between endogenous testosterone levels and CAD. The volume of evidence that links low testosterone levels with CAD has been steadily growing during the past decade. This section is a comprehensive review of clinical literature that examines this relationship.A growing body of evidence suggests that men with lower levels of endogenous testosterone are more prone to develop CAD during their lifetimes.13, 14, 15, 16, 17, 18 However, this is in direct contrast to findings from earlier studies that failed to find any significant association between baseline testosterone levels and the development of CAD.19, 20, 21, 22 There are 2 major potential confounding factors that the older studies generally failed to account for. These factors are the subfraction of testosterone used to perform the analysis and the method used to account for subclinical CAD.Normally, testosterone exists in 2 different subfractions in human serum.23, 24 The biologically inactive form of testosterone is tightly bound to SHBG and is therefore unable to bind to androgen receptors. The biologically inactive fraction of testosterone comprises nearly 68% of the total testosterone in human serum.23, 24 The biologically active subfraction of testosterone, also referred to as bioavailable testosterone, is either loosely bound to albumin or circulates freely in the blood, the latter referred to as free testosterone.23, 24 It is estimated that ≈30% of total serum testosterone is bound to albumin, whereas the remaining 1% to 3% circulates as free testosterone.23 Total testosterone is the sum of all testosterone subfractions. Therefore, it can be argued that using the biologically active form of testosterone to evaluate the association with CAD will produce the most reliable results. However, more research is required to definitively determine whether bioavailable testosterone is superior to free testosterone as a marker of hormone activity.Accounting for both bioavailable testosterone and subclinical CAD, English et al14 found statistically significant lower levels of bioavailable testosterone, free testosterone, and free androgen index in patients with catheterization‐proven CAD compared with controls with normal coronary arteries. These results were confirmed by Rosano et al,17 who showed once again that patients with catheterization‐proven CAD had statistically significant lower levels of bioavailable testosterone. Four additional studies have confirmed these results, although it should be noted that none has accounted for both bioavailable testosterone and subclinical CAD simultaneously (Table 1).13, 15, 16, 18Table 1. Association Between Testosterone Level and Incidence of Coronary Artery DiseaseStudy NameSubfraction of Testosterone Used for AnalysisPrimary End Point Measured (Method)Main Finding of StudyPotential Confounding FactorsArticles showing an association between testosterone level and incident CADZhao et al13 (CCS, n=201)TTCoronary artery disease (H&P, ECG, cardiac catheterization in 27 patients)Men with CAD have lower levels of TT ● BT not used for analysis ● Limited number of subjects have undergone catheterization ● Small sample size English et al14 (CCS, n=90)TT, FT, BT, FAICoronary artery disease (cardiac catheterization)Men with catheterization‐proven CAD have lower levels of FT, BT, and FAI● Small sample sizeDobrzycki et al15 (CCS, n=96)TT, FT, FAICoronary artery disease (cardiac catheterization)Men with catheterization‐proven CAD have lower levels of TT, FT, and FAI ● BT not used for analysis ● Small sample size Akishita et al16 (CS, n=171)TTCardiovascular eventsa (H&P, physician and hospital records)Men with lower levels of endogenous TT are more likely to suffer cardiovascular events ● BT not used for analysis ● Small sample size ● End points other than CAD were pulled in the analysis ● Subjects did not undergo cardiac catheterization Rosano et al17 (CCS, n=129)TT, FT, BTCoronary artery disease (cardiac catheterization)Men with catheterization‐proven CAD have lower levels of TT and BT● Small sample sizeHu et al18 (CCS, n=87)TTCoronary artery disease (cardiac catheterization)Men with catheterization‐proven CAD have lower levels of TT ● BT not used for analysis ● Small sample size Articles not showing an association between testosterone level and incident CADCauley et al19 (CCS, n=163)TT, FTAcute, nonfatal myocardial infarction, death from cardiovascular disease (ECG, hospital records)No difference in TT or FT levels between cases and controls ● BT not used for analysis ● Small sample size ● Subjects did not undergo cardiac catheterization Barrett‐Connor et al20 (CS, n=1009)TTCardiovascular disease or mortality, ischemic heart disease morbidity or mortality (death certificates, hospital records)No statistically significant association between levels of TT and primary end points ● BT not used for analysis ● Subjects did not undergo cardiac catheterization Kabakci et al21 (CCS, n=337)TT, FTCoronary artery disease (cardiac catheterization)No statistically significant difference in FT or TT levels between cases and controls ● BT not used in analysis ● Small sample size ● Suboptimal method used for measurement of FT Arnlov et al22 (PCS, n=2084)TTCardiovascular diseaseb (physician and hospital records)No significant association between levels of endogenous TT and incidence of CAD ● BT not used for analysis ● End points other than CAD were pooled in the analysis ● Subjects did not undergo cardiac catheterization BT indicates bioavailable testosterone; CAD, coronary artery disease; CCS, case–control study; CS, cohort study; ECG, electrocardiogram; FAI, free androgen index; FT, free testosterone; H&P, history and physical exam; PCS, prospective cohort study; TT, total testosterone.aCardiovascular events include stroke, coronary artery disease, sudden cardiac death, and peripheral arterial disease.bCardiovascular disease includes coronary artery disease, myocardial infarction, angina pectoris, coronary insufficiency, death from coronary artery disease, stroke, transient ischemic attack, congestive heart failure, and peripheral vascular disease.On the other hand, some investigators have found no association between endogenous testosterone levels and the incidence of CAD. Although Kabakci et al21 controlled for subclinical CAD by assessing cardiac catheterization results of both cases and controls, they performed their analysis using total and free testosterone levels. This represents a limitation of this study because the authors did not fully account for biologically active testosterone, which includes both free testosterone and testosterone bound to albumin.In conclusion, existing evidence suggests that men with CAD have lower levels of endogenous testosterone,13, 14, 15, 16, 17, 18 and more specifically lower levels of bioavailable testosterone.14, 17 This finding is consistent with evidence that low testosterone levels are associated with risk factors for CAD such as T2DM25, 26 and obesity.27, 28 Currently, it is unknown whether low testosterone levels cause CAD or if they are a consequence of CAD. Caution should be taken in interpreting these results because of the relatively small number of subjects who have been included in the studies. Further prospective epidemiological studies are required to solidify the association between incident CAD and endogenous bioavailable testosterone.Association Between Levels of Endogenous Testosterone and Severity of Coronary Artery DiseaseThere is growing evidence supporting an inverse relationship between the degree of testosterone deficiency and the severity of coronary artery disease. Four investigators have independently demonstrated that in men with CAD, lower levels of endogenous testosterone are associated with more severe CAD (Table 2).15, 17, 29, 30 These results must be interpreted with caution because of the relatively small sample size included in each study and differing study designs. The exact mechanism of action through which testosterone deficiency results in the worsening of CAD is unknown. Testosterone deficiency may cause the worsening of CAD by negatively affecting the components of the metabolic syndrome, such as insulin resistance, hypertension, dyslipidemia, and visceral obesity. The correlation between low testosterone levels and worsening T2DM27 and obesity27 has been well established. The evidence for the association between testosterone and different lipoprotein subfractions is less convincing.31 Testosterone deficiency is also shown to negatively affect carotid intima‐media thickness,32 and therefore it would be reasonable to assume it would have the same deleterious effect on the coronary arteries. To the best of our knowledge, there are no published studies that have investigated the association between testosterone levels and coronary artery intima‐media thickness. Finally, low testosterone may influence the severity of CAD by adversely affecting the mediators of the inflammatory response such as high‐sensitivity C‐reactive protein, interleukin‐6, and tumor necrosis factor–α. Additional investigation using biologically active levels of testosterone is required to further elucidate the association between low testosterone levels and severity of CAD.Table 2. Association Between Testosterone Level and Severity of Coronary Artery DiseaseStudy NameSubfraction of Testosterone Used for AnalysisMethod of Measuring CAD SeverityMain FindingsRemarksDobrzycki et al15 (CCS, n=96)TT, FT, FAIDuke indexaInverse correlation between FT and CAD severityr=−0.69, P=0.048Rosano et al17 (CCS, n=129)TTCoronary artery scorebInverse correlation between TT and CAD severityr=−0.52, P<0.01Li et al29 (CCS, n=803)TTGenisi scorecInverse correlation between TT and CAD severityr=−0.188, P<0.001Phillips et al30 (CCS, n=55)TT, FTVisual estimation of coronary artery occlusion and calculation of mean percent occlusiondInverse correlation between TT and FT levels and CAD severity TT: r=−0.43, P<0.02; FT: r=−0.62, P 2.6 nmol/L.47Existing evidence seems to suggest that lower levels of endogenous testosterone are associated with higher rates of all‐cause mortality and cardiovascular mortality.41 Although results may seem contradictory when total testosterone is used to perform the analysis, results have been consistent when either free or bioavailable testosterone have been used in the analyses.39, 46, 47 In other words, studies have shown that lower levels of endogenous bioavailable testosterone are associated with higher rates of all‐cause and cardiovascular mortality.39, 46, 47 It may be possible that using bioavailable testosterone to perform mortality analysis will yield more accurate results because it prevents the biologically inactive subfraction of testosterone from playing a potential confounding role in the analysis.The exact mechanism of action through which low testosterone increases mortality is currently unknown. Testosterone may be acting directly on the cardiovascular system by a mechanism that is as yet undiscovered. On the other hand, testosterone could be functioning as a marker for an underlying disease entity that results in increased mortality risk. A list of studies that analyzed the association between testosterone level and mortality is presented in Table 3.Table 3. Association Between Levels of Endogenous Testosterone and MortalityStudy NameSubfraction of Testosterone Used for AnalysisSample SizeSample Age Range/Sample Mean Age (Years)Mean Follow‐up Period (Years)Major FindingRemarksHaring et al35 (CS, n=1954)TT195420 to 79/58.77.2Low TT is associated with increased risk of mortality from all causes and CV disease ● HR of low TT for all‐cause mortality, 1.92 95% CI, 1.18 to 3.14; P<0.001 ● HR of low TT for CV mortality, 2.56; 95% CI, 1.15 to 6.52; P<0.05 Khaw et al36 (CCS, n=11 606)TT11 60640 to 79/67.37Low TT is associated with higher risk of all‐cause and CV mortality. Same trend was noted for CHD mortality but statistical significance was not achieved ● OR of low TT for all‐cause mortality, 0.59; P<0.001 ● OR of low TT for CV mortality, 0.53; P<0.01 Menke et al39 (CS, n=1114)TT, FT, BT1114≥20/4016Decrease in FT and BT from 90th to 10th percentile is associated with increased risk of all‐cause and CV mortality during the first 9 years of follow‐up ● HR of FT decrease for all‐cause mortality, 1.43; 95% CI, 1.09 to 1.87 ● HR of BT decrease for all‐cause mortality, 1.52; 95% CI, 1.15 to 2.02 ● HR of FT decrease for CV mortality, 1.53; 95% CI, 1.05 to 2.23 ● HR of BT decrease for CV mortality, 1.63; 95% CI, 1.12 to 2.37 Vikan et al40 (CS, n=1568)TT, FT1568Not reported/59.611.224% Higher risk of all‐cause mortality for men with low FT levels● HR of low FT for all‐cause mortality, 1.24; 95% CI, 1.01 to 1.54Tivesten et al42 (CS, n=3014)TT, FT2639 with TT; 2618 with FT69 to 80/75.44.5Increasing levels of TT and FT are associated with decreasing risk of all‐cause mortality ● HR of high TT for all‐cause mortality, 0.59; P<0.001 ● HR of high FT for all‐cause mortality, 0.50; P<0.001 Shores et al44 (CS, n=858)TT858≥40/61.44.3Low TT is associated with higher risk of all‐cause mortality● HR of low TT for all‐cause mortality, 1.88; P<0.001Laughlin et al46 (CS, n=794)TT, BT79463 to 78.9/71.211.8Low TT and BT are associated with higher risk of all‐cause and CV mortality ● HR of low TT for all‐cause mortality, 1.44; P<0.002 ● HR of low BT for all‐cause mortality, 1.50; P<0.001 ● HR of low TT for CV mortality, 1.38; 95% CI, 1.02 to 1.85 ● HR of low BT for CV mortality, 1.36; 95% CI, 1.04 to 1.79 Malkin et al47 (FU, n=930)TT, BT930Not reported6.9Low BT is inversely associated with time to all‐cause and vascular mortality ● HR of low BT for all‐cause mortality, 2.2; 95% CI, 1.4 to 3.6; P<0.0001 ● HR of low BT for vascular mortality, 2.2; 95% CI, 1.2 to 3.9; P=0.007 BT indicates bioavailable testosterone; CAD, coronary artery disease; CCS, case–control study; CHD, coronary heart disease; CI, confidence interval; CS, cohort study; CV, cardiovascular; FAI, free androgen index; FT, free testosterone; FU, follow‐up study; HR, hazard ratio; OR, odds ratio; TT, total testosterone.Testosterone, Angina Threshold, and Coronary Artery Vasomotor RegulationTestosterone replacement therapy for the treatment of angina pectoris is not a new concept. The earliest published material on this matter dates to the late 1930s. In 1942 Lesser reported the results of his experiments performed on 92 men and 8 women, all of whom suffered from exertional angina.48 Lesser treated all subjects with varying dosages of intramuscular testosterone propionate over a period of 4 to 5 months. At the completion of the study protocol, 51 subjects reported "marked improvement" in their symptoms, 40 subjects reported "moderate improvement," and 9 subjects reported no improvement in symptoms. Lesser defined marked improvement as an angina‐free period of 2 months after the completion of the study, whereas moderate improvement was defined as a 50% reduction in the number of angina attacks compared with the period prior to initiation of testosterone replacement. Lesser did not provide statistical analysis of his data, and therefore the significance of his findings cannot be validated.48 Other studies from this era also produced similar findings.49 Although most of the earlier studies lacked statistical analysis and their study designs would be considered subpar compared with current standards, the concept that testosterone replacement therapy improves angina has yet to be proven wrong. In more recent studies, 3 randomized, placebo‐controlled trials demonstrated that administration of testosterone improves myocardial ischemia in men with CAD. English et al,50 Rosano et al,51 and Webb et al52 all showed that in men with CAD, testosterone prolongs the time to exercise‐induced ST‐segment depression, as measured on treadmill stress testing. The improvement in myocardial ischemia was shown to occur in response to both acute and chronic testosterone therapy and seemed to be independent of whether an intravenous or transdermal formulation of testosterone was used. One of the studies that also gathered data on quality‐of‐life measures reported statistically significant improvement in pain perception as well as role limitation due to physical problems in the testosterone therapy group.50 In 2 of the studies that correlated baseline testosterone levels with the amount of change in time to 1‐mm ST‐segment depression, both studies showed that men with lower levels of baseline endogenous testosterone had greater improvement in time to exercise‐induced 1‐mm ST‐segment depression.50, 51 Specifically, English et al, who randomized nonhypogonadal men with chronic stable angina to either 5 mg of testosterone daily by transdermal patch or control for a duration of 2 weeks, showed that administration of testosterone increased the time to 1‐mm ST‐segment depression on exercise stress testing by 69 seconds.50 Rosano et al, who administered 2.5 mg of testosterone intravenously 30 minutes prior to exercise stress testing to nonhypogonadal men with coronary artery disease, showed that testosterone increased the time to 1‐mm ST‐segment depression by 108 seconds and total exercise time by 90 seconds.51 Moreover, Rosano et al also discovered that the amount of change in time to 1‐mm ST‐segment depression was independent of the peak testosterone level that was achieved.51Evidence suggests that testosterone increases angina threshold in men with CAD by causing vasodilation of coronary arteries. Webb et al53 demonstrated vasodilation of the coronary arteries in response to intracoronary infusion of testosterone in men with CAD. Three other investigators documented vasodilation of the brachial artery in response to testosterone infusion,54, 55, 56 whereas others have shown coronary artery dilation in response to testosterone in rabbit,57 canine,58 and swine59 models. However, the exact mechanism of action through which testosterone exerts its effect on coronary vasculature is unknown.Webb et