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Two recent studies raised new concerns regarding cardiovascular (CV) risks with testosterone (T) therapy. This article reviews those studies as well as the extensive literature on T and CV risks. A MEDLINE search was performed for the years 1940 to August 2014 using the following key words: testosterone, androgens, human, male, cardiovascular, stroke, cerebrovascular accident, myocardial infarction, heart attack, death, and mortality. The weight and direction of evidence was evaluated and level of evidence (LOE) assigned. Only 4 articles were identified that suggested increased CV risks with T prescriptions: 2 retrospective analyses with serious methodological limitations, 1 placebo-controlled trial with few major adverse cardiac events, and 1 meta-analysis that included questionable studies and events. In contrast, several dozen studies have reported a beneficial effect of normal T levels on CV risks and mortality. Mortality and incident coronary artery disease are inversely associated with serum T concentrations (LOE IIa), as is severity of coronary artery disease (LOE IIa). Testosterone therapy is associated with reduced obesity, fat mass, and waist circumference (LOE Ib) and also improves glycemic control (LOE IIa). Mortality was reduced with T therapy in 2 retrospective studies. Several RCTs in men with coronary artery disease or heart failure reported improved function in men who received T compared with placebo. The largest meta-analysis to date revealed no increase in CV risks in men who received T and reduced CV risk among those with metabolic disease. In summary, there is no convincing evidence of increased CV risks with T therapy. On the contrary, there appears to be a strong beneficial relationship between normal T and CV health that has not yet been widely appreciated.
In November 2013 and January 2014, 2 studies were published reporting increased cardiovascular (CV) risks in men who received testosterone (T) prescriptions.
These articles gained wide media attention. Media coverage of these studies was frequently combined with data indicating rapidly increased sales of T products,
raising concerns that the pharmaceutical industry was promoting a treatment associated with important risks. This view was captured best by a New York Times editorial entitled “Overselling Testosterone, Dangerously.”
The impact of these studies on patient management and the ensuing public attention has been substantial. Men discontinued treatment, occasionally criticizing their physicians for putting their health at risk; some physicians stopped prescribing T products, and others warned against treatment of T deficiency (TD) (also called hypogonadism or, more casually, low T). The Endocrine Society issued a statement cautioning against the use of T therapy in older men and in men with a history of coronary artery disease (CAD).
Plaintiff attorneys began a nationwide campaign seeking cases of myocardial infarctions (MIs) and strokes in men who had used T products for a class action lawsuit. These concerns thrust T therapy into the news, where the reported CV risks anchored a variety of unrelated concerns regarding other aspects of T therapy, such as overuse and abuse, false claims by antiaging medicine, profiteering by low-T clinics, and the failure of men to accept the rigors of natural aging.
It is beyond the scope of this article to address these various issues. Instead, we wish to address the key scientific question, namely, whether T therapy is associated with increased CV risks. This review encompasses an analysis of the literature previously submitted by us to the FDA and to the European Medicines Agency to assist with their own investigations of this topic. This article provides in-depth analysis of studies suggesting increased CV risks with T therapy, a historical perspective, and a systematic literature review. Because of the large number of studies reviewed, much of the information is presented in tables, with text limited to summaries of data.
There are no large, long-term, placebo-controlled randomized clinical trials in the field of T therapy to provide definitive conclusions about CV risk. Nonetheless, there exists a rich literature spanning many decades that provides valuable information. As described in more detail subsequently, the 2 recent articles contradict this literature, and on careful review, neither provides credible evidence of increased CV risks. Only 2 additional studies are generally cited as support for that view. In contrast, many dozens of studies, including a modest number of randomized controlled trials (RCTs), indicate that low serum T concentrations are associated with increased CV risk and mortality and that T therapy may have clinically relevant CV benefits. This last point will be new to many readers. A recently published meta-analysis of 75 placebo-controlled studies, the largest to date, found no evidence of increased CV risk with T therapy and clear evidence of improved metabolic profiles.
Given the personal suffering of men with TD as well as the public health burden of TD, the recent controversy regarding T and CV disease presents an important opportunity to understand the science underlying this critical medical issue.
Background
Testosterone deficiency is a clinical syndrome characterized by a set of signs and symptoms in combination with low serum T concentrations.
International Society of Andrology (ISA); International Society for the Study of Aging Male (ISSAM); European Association of Urology (EAU); European Academy of Andrology (EAA); American Society of Andrology (ASA) Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations.
Symptoms include decreased libido, erectile dysfunction, difficulty achieving orgasm, reduced intensity of orgasm, fatigue, decreased energy, depressed mood, irritability, and decreased sense of well-being. Objective signs include anemia, decreased bone density, reduced muscle strength and mass, increased body fat mass (both visceral and total), and weight gain.
International Society of Andrology (ISA); International Society for the Study of Aging Male (ISSAM); European Association of Urology (EAU); European Academy of Andrology (EAA); American Society of Andrology (ASA) Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations.
Androgen deprivation therapy, used in the treatment of advanced prostate cancer, causes profound TD and is associated with negative changes in body composition as well as increased risk of incident diabetes mellitus.
Testosterone Gel Study Group Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men.
Testosterone replacement therapy with long-acting testosterone undecanoate improves sexual function and quality-of-life parameters vs. placebo in a population of men with type 2 diabetes.
Testosterone replacement therapy with long-acting testosterone undecanoate improves sexual function and quality-of-life parameters vs. placebo in a population of men with type 2 diabetes.
Effect of long-acting testosterone undecanoate treatment on quality of life in men with testosterone deficiency syndrome: a double blind randomized controlled trial.
Long-term testosterone treatment in elderly men with hypogonadism and erectile dysfunction reduces obesity parameters and improves metabolic syndrome and health-related quality of life.
Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study.
Testosterone Gel Study Group Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men.
Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study.
Effect of testosterone supplementation with and without a dual 5α-reductase inhibitor on fat-free mass in men with suppressed testosterone production: a randomized controlled trial.
Effects of long-term testosterone therapy on patients with “diabesity”: results of observational studies of pooled analyses in obese hypogonadal men with type 2 diabetes.
BLAST Study Group Testosterone replacement therapy improves metabolic parameters in hypogonadal men with type 2 diabetes but not in men with coexisting depression: the BLAST study.
Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study.
Effect of testosterone supplementation with and without a dual 5α-reductase inhibitor on fat-free mass in men with suppressed testosterone production: a randomized controlled trial.
Effects of long-acting testosterone undecanoate on bone mineral density in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 36 months controlled study.
Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men.
Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study.
Fifty-two-week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone.
Effects of long-term testosterone therapy on patients with “diabesity”: results of observational studies of pooled analyses in obese hypogonadal men with type 2 diabetes.
Hypogonadal obese men with and without diabetes mellitus type 2 lose weight and show improvement in cardiovascular risk factors when treated with testosterone: an observational study.
Effects of long-term testosterone therapy on patients with “diabesity”: results of observational studies of pooled analyses in obese hypogonadal men with type 2 diabetes.
BLAST Study Group Testosterone replacement therapy improves metabolic parameters in hypogonadal men with type 2 diabetes but not in men with coexisting depression: the BLAST study.
Hypogonadal obese men with and without diabetes mellitus type 2 lose weight and show improvement in cardiovascular risk factors when treated with testosterone: an observational study.
Biochemical confirmation of TD has traditionally been made on the basis of low serum concentrations of total T (TT). Although no specific value reliably distinguishes men who will respond to treatment from those who will not, recommended thresholds for low TT range from 300 ng/dL (10.4 nmol/L)
Because a majority of circulating T is rendered biologically unavailable due to tight binding to sex hormone–binding globulin (SHBG), the unbound fraction called free T and/or the portion of T weakly bound to albumin may be more indicative of a man’s true androgen status.
These 2 fractions together represent bioavailable T. Men with high-normal or elevated SHBG concentrations may have TT concentrations within the normal range yet may still have TD due to reduced free T concentrations. This issue may be particularly relevant for older men because SHBG levels increase with age.
Levels below 65 to 100 pg/mL (<174-288 pmol/L) for calculated free T and 0.8 to 1.5 ng/dL (27-52 pmol/L) for directly measured free T have been used clinically to identify men who are candidates for treatment.
International Society of Andrology (ISA); International Society for the Study of Aging Male (ISSAM); European Association of Urology (EAU); European Academy of Andrology (EAA); American Society of Andrology (ASA) Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations.
However, laboratory-provided reference ranges are problematic because they are not clinically based and vary widely between assays, and even among laboratories using the same assays.
The prevalence of symptomatic TD ranges from 2.1% to 12.8% in middle-aged to older men, with an incidence of 12 new cases per 1000 person-years in the United States and Europe.
Populations at high risk for low serum T levels include men with type 2 diabetes, obesity, chronic obstructive pulmonary disease, infection with human immunodeficiency virus, and chronic opioid use, all with prevalence rates greater than 30%.
This increase has led to concerns that T products are overprescribed because of aggressive marketing. However, as recently as 2007, the FDA indicated that as few as 5% of the hypogonadal population was treated,
The increase in T prescriptions seems to have resulted from increased awareness of TD and the benefits of T therapy among both physicians and patients, coupled with reduced concern regarding prostate cancer risk.
Although it has been asserted that direct-to-consumer marketing is responsible for this growth, the evidence would suggest otherwise, as 2010 industry data failed to include any T products within the 25 most-marketed drugs in the United States.
Whereas it was once believed that TD only occurred in association with several rare disorders, such as pituitary tumors, Klinefelter syndrome, or mumps orchitis, it is now understood that TD is common and often idiopathic. Symptoms and signs result directly from reduced serum concentrations of T, regardless of etiology, and can be induced experimentally in healthy volunteers of all ages simply by reducing serum T concentrations.
The relatively high prevalence of TD in middle-aged and older men has given rise to the concept of male menopause, or andropause. Although these terms have some conceptual appeal, TD differs importantly from menopause in that most men are unaffected, and the onset is gradual over an extended time course.
and several of the earliest reports documented benefits specifically for CV disease. From the late 1930s into the 1950s, several studies reported marked benefits of T therapy in patients with peripheral vascular disease
described 100 consecutive patients (92 men and 8 women) ranging from 34 to 77 years of age with angina pectoris who received T therapy with follow-up ranging from a few months to 5 years. Improvement was noted in 91%, with no appreciable improvement in patients treated with placebo.
A wealth of modern data accumulated over the past 2 decades has generally revealed that a low serum T level is associated with increased risks of atherosclerosis, CV risk factors, and mortality and that T therapy has beneficial effects on multiple risk factors and risk biomarkers related to these clinical conditions. Notably, TD has been projected to be involved in the development of approximately 1.3 million new cases of CV disease, 1.1 million new cases of diabetes, and over 600,000 osteoporosis-related fractures.
Over a 20-year period, TD has been estimated to be directly responsible for approximately $190 to $525 billion in inflation-adjusted US health care expenditures.
In addition, longitudinal models predict increased outpatient visits and costs related to low baseline serum T levels independent of socioeconomic and lifestyle factors; even when controlling for age, men aged 20 to 79 years at baseline with low serum T levels had 29% more outpatient visits and 38% higher outpatient costs at 5-year follow-up.
Numerous intervention studies have consistently found improvements in CV risk factors such as fat mass, obesity, waist circumference, blood pressure, and glycemic control. These important findings provide a reasonable biological mechanism to explain the frequently observed outcome of increased mortality among men with the lowest quartiles or quintiles of serum T or with frank TD.
Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European Prospective Investigation Into Cancer in Norfolk (EPIC-Norfolk) prospective population study.
In older men an optimal plasma testosterone is associated with reduced all-cause mortality and higher dihydrotestosterone with reduced ischemic heart disease mortality, while estradiol levels do not predict mortality.
Importantly, TD in older men is associated with increased risk of death during the 20 years after diagnosis, independent of multiple traditional risk factors and several preexisting health conditions.
Small randomized, placebo-controlled T trials have documented reduction in carotid intima-media thickness with T therapy, raising the possibility that normalizing serum T may actually cause reversal of atherosclerosis in critical vascular beds. Moreover, 2 studies published within the past 2 years, one in a Veterans Administration population
found mortality reduced by half in men with TD who received T prescriptions compared with similar men who did not, It was therefore surprising that publication of 2 retrospective studies reporting increased risks of CV adverse events would cause such great concern. In one of these studies, Vigen et al
reported increased rates of MIs, strokes, and deaths in men who received T prescriptions compared with untreated men; this study used unvalidated statistical methodology that reversed the raw data, which actually revealed that the percentage of adverse events in T-treated men was lower by half compared with untreated men.
reported an increased rate of nonfatal MI up to 90 days after receipt of a T prescription compared with the previous 12 months. However, MI rates postprescription were low, there was no control group, and methodological issues again rendered the study results highly questionable.
Although an advisory committee meeting was scheduled for September 17, 2014, the FDA had already made public its own analysis of the literature in its denial of a petition by the group Public Citizen to add black box warnings and other restrictions to T products.
The FDA’s comments are included where appropriate in the analysis that follows.
Methods
A MEDLINE search was performed for the years 1940 to August 2014 using the following key words: testosterone, androgens, human, male, cardiovascular, stroke, cerebrovascular accident, myocardial infarction, heart attack, death, and mortality. Additional studies were sought by examining publications with their own literature reviews. Tables were created with results provided by abstracts or from the full text of the article, depending on the adequacy of abstracted information.
A review of the literature was performed for 9 specific topics related to T and CV risks: mortality; incident CAD; severity of CAD; ischemic stroke; carotid intima-media thickness; obesity/fat mass; lipid profiles; glycemic control; and inflammatory markers. A summary statement was made regarding the interpretation of relevant studies in those areas, and level of evidence supporting that conclusion was adjudicated by 2 authors (M.M., A.T.).
Analysis
In contrast to many dozens of studies documenting the beneficial CV effects of T therapy in humans, there appear to be only 4 articles that suggest increased CV risk. These 4 articles were also identified by the FDA analysis. These articles are the 2 retrospective large dataset analyses of Vigen et al
and a report of incidental CV adverse events in a placebo-controlled T gel study designed to assess muscular and functional benefits in elderly, frail men with mobility limitations by Basaria et al.
Although few in number, these studies have garnered considerable attention in the medical literature and lay press, and therefore merit individual analysis here.
conducted a retrospective analysis of men who had undergone coronary angiography within the Veterans Administration health care system. The authors reported that the overall rate of MI, stroke, and death in men with serum T levels less than 300 ng/dL (to convert to nmol/L, multiply by 0.0347) was higher in men who received a T prescription compared with untreated men. Although no statistically significant differences were noted at years 1, 2, or 3, the overall rate of events over the course of the study was reported to be significantly higher (29%) in T-treated men.
Strangely, the actual rate of adverse events was only half as great in the T group (123 events in 1223 men at risk, 10.1%) as in the untreated group (1587 events in 7486 men, 21.2%) (Figure).
The authors failed to acknowledge this fact and came to an opposite interpretation of the data based on complex statistics that included adjustment for more than 50 variables. The methodology in this study, ie, stabilized inverse propensity treatment weighting applied to Kaplan-Meier curves with time as a covariate, was described in an article by senior author Michael P. Ho just a year earlier (2012) as follows: “Clearly, assessing and confirming adequate covariate balance in IPTW time-varying models is challenging and needs further study… Further work with simulations and contrasts to other methods and other study applications would help elucidate the advantages and disadvantages of this approach.”
that these major methodological concerns have been resolved and that the methodology itself is accurate or accepted by other investigators.
FigureActual percentage of individuals who experienced an adverse cardiovascular event in the testosterone (T)-treated and untreated groups in the study by Vigen et al.
The authors reported a higher rate of adverse events in the T-treated group using inverse stabilized propensity weighting in which an event was counted as more than 1 event in the T-treated group and less than 1 event in the untreated group. MI = myocardial infarction.
This article has already undergone 2 official corrections. The first, published January 15, 2014, was for misreporting of primary results as “absolute risk,” a term that suggests the results were based on raw data.
In response to criticism following publication, the article was corrected to replace the term absolute risk with Kaplan-Meier estimated cumulative percentages with events, a term that more accurately reflects the highly statistical nature of the results. On March 5, 2014, JAMA published a second correction.
In response to a letter challenging the exclusion of 1132 men who had suffered adverse events in the non-T group, the authors revealed they had made a series of errors. The number of men in this excluded group was changed from 1132 to 128 men, a difference of greater than 1000 men. The value for a second group was found to be incorrect by more than 900 men. Most astonishingly, the all-male study group was found to include nearly 10% women. In response to these errors, 29 international medical societies and more than 160 physician-scientists from 32 countries petitioned JAMA to retract this article, citing “gross data mismanagement and contamination” that rendered the study “no longer credible.”
In summary, this study used an unvalidated methodology to reverse the results of raw data, which revealed a lower percentage of adverse events in the T-treated group compared with untreated men. Putting aside the multiple disturbing data errors that undermine the integrity of the study, this lower percentage of adverse CV events in the T-treated group is consistent with the results of 2 prior studies that reported mortality reduced by half in T-treated men compared with untreated men.
was as follows: “Given the described limitations of the study by Vigen et al it is difficult to attribute the reported findings to testosterone treatment.”
was a retrospective study of a health insurance database that reported rates of nonfatal MI in the period up to 90 days after a T prescription and compared these rates to MI rates in the previous 12 months. The postprescription period was the time to first prescription refill, which for an unspecified number of men would have been 30 days rather than 90 days. The authors reported the rate ratio of MI postprescription to preprescription was 1.36, and the rate in men older than 65 years was 2.19. In comparison, no increase in MI rate was noted for men who received a prescription for a phosphodiesterase type 5 inhibitor (PDE5i).
Because the source was an insurance claims database, available information was limited to diagnosis codes, procedure codes, and prescriptions. There was no information available regarding several standard CV risk factors, such as diabetes, hypertension, hyperlipidemia, smoking history, or obesity, and no information concerning any blood test results, including serum T, or lipid profiles. The weakness of the dataset as an investigative tool for assessment of CV risk is underscored by the fact that the end point in the study, nonfatal MI, was determined solely by the use of an insurance diagnosis code without verification that MI occurred and without measures to increase the likelihood of capturing a true event, such as limiting events to the primary diagnosis code at hospital discharge.
The post–T prescription MI rate reasonably reflects the naturally occurring MI rate in this population, albeit with the aforementioned caveats regarding the accuracy of this type of database investigation. However, because men were included in the study on the basis of real-world receipt of a T prescription, the pre–T prescription MI reflected how often health care providers were willing to prescribe T to men with a recent (within 12 months) MI. Any reluctance to prescribe T to men with recent MI would result in a reduced preprescription MI rate. The rates of MI in the preprescription and postprescription periods thus measure different things, and the comparison is therefore meaningless.
Moreover, the reported MI rates post–T prescription were all low, overall and for all subgroups. For example, the overall postprescription MI rate reported by Finkle et al
was 4.75 events per 1000 person-years. This result compares with a rate of 13 expected MIs per 1000 person-years using the National Institutes of Health heart attack risk calculator, inputting age 54 years (the mean age of the study participants) and favorable risk parameters (nonsmoker; total cholesterol, 230 mg/dL [to convert to mmol/L, multiply by 0.0259]; high-density lipoprotein [HDL] cholesterol, 40 mg/dL [to convert to mmol/L, multiply by 0.0259]; systolic blood pressure, 140 mm Hg).
National Institutes of Health, National Heart, Lung, and Blood Institute. Risk assessment tool for estimating your 10-year risk of having a heart attack. National Heart, Lung, and Blood Institute website. http://cvdrisk.nhlbi.nih.gov/calculator.asp. Updated May, 2013. Accessed April 21, 2014.
The observed MI rate among men who received a T prescription was thus approximately one-third the expected rate. In the absence of a control group of men who were untreated, it is impossible to determine whether these reported MI rates were higher, lower, or unchanged in association with a T prescription.
Finally, the comparison with men who received a PDE5i prescription is uninterpretable. These were 2 dissimilar groups treated with dissimilar medications for dissimilar indications. Phosphodiesterase type 5 inhibitors are known to have vasodilatory properties, and one medication in this class, sildenafil, is approved for treatment of pulmonary hypertension, confounding any comparison because of the possibility that PDE5i’s may have beneficial effects on CV risk. This is a classic case of comparing apples and oranges.
is that TD itself has been identified as a risk factor for CV events (reviewed in the “Testosterone and Mortality section). Given the short T exposure time of 30 to 90 days, one unexplored possibility is that any observed increased risk of MI was due to the underlying condition rather than from the treatment. For this reason, we agree with the FDA analysis, which concluded that “it is difficult to attribute the increased risk for non-fatal MI seen in the Finkle study to testosterone alone and not consider that the study participants might have remained hypogonadic and thus at higher risk for non-fatal MI.”
conducted a prospective randomized trial designed to investigate whether T gel provided greater muscular and functional benefits than placebo in a population of frail elderly men treated for 6 months. The study did indeed find a benefit of T treatment over placebo for muscular and functional responses but was terminated early because of the observation of increased adverse events categorized as “cardiovascular” in the treatment arm. There were 23 of these events in the T arm and 5 in the placebo arm.
However, this study was not designed to investigate CV events, and none of these events were primary or secondary end points. Most of the reported “events” were incidentally noted, subjective, or of questionable clinical importance, such as palpitations, pedal edema, and premature ventricular contractions. None of these adverse events were defined before study enrollment, and there was no attempt to systematically investigate all participants for the presence of any of these events. The most frequently reported adverse event was pedal edema, with 5 cases in the T group and none in the placebo group. Given that the placebo group was composed of more than 100 frail elderly men with multiple comorbidities, it seems unlikely that none of them had any degree of pedal edema. This flaw underscores concerns about the interpretation of these data by Basaria et al
as indicative of true CV risk rates because it violated foundational concepts in clinical trials, ie, defined end points and systematic data acquisition.
Four major adverse cardiac events (MACE) occurred: 1 death, 2 MIs, and 1 stroke, all of which occurred in the T group. Although troubling, this asymmetry is not uncommon with rare events in clinical trials. In a similar study in frail elderly men performed in the United Kingdom, there were 2 MACE (1 death, 1 MI), both occurring in the placebo group.
Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study.
concluded, “The lack of a consistent pattern in these events and the small number of overall events suggest the possibility that the differences detected between the two trial groups may have been due to chance alone.” A subsequent analysis suggested that events were associated with higher serum concentrations of T achieved with treatment using higher than approved doses of T, contrary to the recommendations of the Endocrine Society guidelines.
It is impossible to conclude from this study that T prescriptions confer an increased risk of CV events. The FDA concluded, “The Basaria study does appear to show an empirical dose-dependent association between testosterone and cardiovascular risk, but it was non-conclusive because of the small sample size and small number of events reported in the study, as well as the limitations with respect to confirming the events. The authors of this study have explicitly indicated that the differences between the groups in cardiovascular adverse events might have been due to chance alone.”
reported that more CV events occurred in men who received T compared with those who received placebo. This study is the only one of several meta-analyses and systematic reviews to suggest any increased risk with T therapy. As with all meta-analyses, results are greatly influenced by the definitions of end points of interest and the selection of studies. In this case, the authors specifically included only studies in which one or more CV events were reported, meaning that studies without any CV events were excluded. This selection process exaggerates the apparent rate of events and distorts absolute differences in event rates between groups. In addition, just 2 of the 27 studies contributed 35% of all CV events in the T arm.
The disproportionate influence of these 2 studies on the outcome of the meta-analysis merits closer scrutiny. One is the study by Basaria et al
in which a nonapproved oral formulation of micronized T was administered at a remarkably high dose of 600 mg/d to men with cirrhosis of the liver, resulting in serum T concentrations exceeding 4000 ng/dL (approximately 140 nmol/L) in a quarter of the T group and levels as high as 21,000 ng/dL (745 nmol/L), a value approximately 20 times the upper limit of the normal range. Because these oral forms of T are known to cause liver toxicity via a first-pass effect, it should be no surprise that markedly supraphysiologic T doses in a hepatically compromised population would prove harmful. Moreover, the authors appear to have categorized any bleeding event as “cardiovascular,” including the most frequently observed cause of death in this study, bleeding from esophageal varices. The authors listed 21 events as CV, yet only 1 (MI) could reasonably be considered as CV. This trial has little relevance to the question as to whether the clinical use of T therapy increases CV risks. Its inclusion and misreporting led to distorted results.
the rates of adverse CV events in the T and placebo groups were similar, with a slightly lower rate in the T group (78 events in 1599 men [4.88%] vs 60 events in 1174 men [5.1%], respectively). It should be underscored that this is the only one of several previously published meta-analyses and systematic reviews to report increased risk with T treatment.
included 3016 men treated with T and 2446 treated with placebo for a mean treatment duration of 34 weeks. They found no significant association between T therapy and CV events, either as single events or as combined CV end points. Studies in men with metabolic derangements revealed a protective effect of T treatment.
None of the 4 studies cited as evidence supporting an increased CV risk with T administration provide compelling evidence of increased risk. Indeed, the articles by Vigen et al
could each arguably be described as documenting protective effects of T therapy on CV risk because the percentage of events was lower by half in the former and overall MI rates were only a fraction of expected rates in the latter. Events reported by Basaria et al
appear to be due to the inclusion of questionable events and studies, and their conclusions are contradicted by several other meta-analyses.
Review of Existing Literature
Any objective assessment of the literature regarding T and CV effects must recognize a broad, rich literature in which numerous studies reveal increased CV concerns with TD and improvement in a variety of CV risk factors and some CV outcomes with T therapy. That literature has been summarized and tabulated and is included here in Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9. Summary statements and levels of supporting evidence are provided in Table 10.
Table 2Observational Studies of Serum Testosterone Concentrations and Mortality
Testosterone deficiency is associated with substantially higher risks of all-cause and cardiovascular mortality, to which both the level of testosterone and the presence of sexual symptoms contribute independently
HR of low TT <8 nmol/L (irrespective of symptoms) for all-cause mortality, 2.3 (95% CI, 1.2-4.2) HR of low TT <8 nmol/L and FT <220 pmol/L for all-cause mortality, 5.5 (95% CI, 2.7-11.4) HR with 3 sexual symptoms (irrespective of serum testosterone level; compared with asymptomatic men), 3.2 (95% CI, 1.8-5.8) Similar risks observed for cardiovascular mortality
Association of sex steroids, gonadotrophins, and their trajectories with clinical cardiovascular disease and all-cause mortality in elderly men from the Framingham Heart Study.
Higher baseline TT concentrations were associated with lower mortality risk at 5 y Correction for multiple statistical testing (P<.005) rendered this association statistically nonsignificant Repeated analyses at 10-y follow-up revealed no significant association between sex steroids, gonadotropins or their trajectories and mortality
HR (per quartile increment) of high FT for all-cause mortality, 0.74 (95% CI, 0.56-0.98)
Low testosterone levels predict an increase in all-cause mortality during long-term follow-up. Testosterone replacement may improve survival in hypogonadal men with type 2 diabetes
Mortality increased in the low testosterone group (17.2%) compared with the normal testosterone group (9%; P=.003) when controlled for covariates In Cox regression model, multivariate-adjusted HR for decreased survival was 2.02 (95% CI, 1.2-3.4; P=.009). TRT (mean duration, 41.6±20.7 mo; n=64) associated with a reduced mortality of 8.4% compared with 19.2% (P=.002) in the untreated group (n=174) Multivariate-adjusted HR for decreased survival in the untreated group was 2.3 (95% CI, 1.3-3.9; P=.004)
Lower free testosterone (and higher SHBG and LH levels) were associated with all-cause mortality In cause-specific analyses, lower free testosterone (and higher LH) predicted CVD mortality, while higher SHBG predicted non-CVD mortality
HR of low FT for all-cause mortality, 1.62 (95% CI, 1.20-2.19) for 100 vs 280 pmol/L HR of low FT for CVD mortality, 1.71 (95% CI, 1.12-2.62) for 100 vs 280 pmol/L
Measured TT levels may help detect high-risk individuals for potential therapeutic interventions and improve mortality risk assessment and outcome
HR for all-cause mortality in men with kidney dysfunction, 1.4 (95% CI, 1.02-1.92) HR for all-cause mortality in men with kidney dysfunction and low TT, 2.52 (95% CI, 1.08-5.85)
Testosterone deficiency in male HD patients is associated with increased CVD and all-cause mortality Increased arterial stiffness may be a possible mechanism explaining this association
Patients with testosterone deficiency had increased CVD and all-cause mortality, even after adjustment for age, body mass index, serum albumin and C-reactive protein levels, prevalent CVD, and HD duration Testosterone levels were inversely related to PWV (r=−0.441; P<.001) The association of testosterone with CVD mortality, but not with all-cause mortality, was lost after adjusting for PWV, an index of arterial stiffness
Testosterone deficiency is independently associated with cardiovascular comorbidity and death in logistic regression analyses Testosterone deficiency is a common finding among male patients with ESRD, and it is independently associated with inflammation, cardiovascular comorbidity and outcome
OR of low TT for cardiovascular comorbidity was 2.51 (95% CI, 1.32-4.76) and for death was 2.0 (95% CI, 1.01-3.97)
2010 (Third National Health and Nutrition Examination Survey)
TT, BT, FT
1114
≥20/40
16
Population-based, United States
Decrease in FT and BT from 90th to 10th percentile is associated with increased risk of all-cause and CV mortality during the first 9 y of follow-up
HR of FT decrease for all-cause mortality, 1.43 (95% CI, 1.09-1.87) HR of BT decrease for all-cause mortality, 1.52 (95% CI, 1.15-2.02) HR of FT decrease for CV mortality, 1.53 (95% CI, 1.05-2.23) HR of BT decrease for CV mortality, 1.63 (95% CI, 1.12-2.37)
Testosterone levels are associated with a higher mortality of MACE Identification of low testosterone levels identifies patients with an increased cardiovascular risk
Proportion of lethal events among MACE was significantly higher in hypogonadal patients, using either 10.4 nmol/L (300 ng/dL) or 8 nmol/L (230 ng/dL) thresholds After adjustment for age and Chronic Disease Score in a Cox regression model, only the association between incident fatal MACE and testosterone <8 nmol/L (230 ng/dL) was confirmed (HR, 7.1 [95% CI, 1.8-28.6]; P<.001)
Gonadal and adrenal androgen deficiencies as independent predictors of increased cardiovascular mortality in men with type II diabetes mellitus and stable coronary artery disease.
A low level of testosterone was independently related to total short-term mortality
OR for TT quartiles 2,3, and 4 vs 1: 0.82 (95% CI, 0.67-1.03), 0.67 (95% CI, 0.52-0.86), and 0.70 (95% CI, 0.56-0.89), respectively (P trend, <.01) The mean level of TT = 4.1±2.9 ng/mL All nonsurvivors had TT ≤3 ng/mL
In men undergoing hemodialysis, testosterone concentrations inversely correlate with all-cause and CVD-related mortality, as well as with markers of inflammation. Hypogonadism may be an additional treatable risk factor for patients with chronic kidney disease
HR for TT in the lowest tertile for all-cause mortality, 2.03 (95% CI, 1.24-3.31) HR for TT in the lowest tertile for CVD mortality, 3.19 (95% CI, 1.49-6.83) Increased risk with low TT persisted after adjustment for age, SHBG, previous CVD, diabetes, ACEi/ARB treatment, albumin, and inflammatory markers but was lost after adjustment for creatinine
Serum TT in elderly men is inversely associated with mortality Higher endogenous testosterone levels have a favorable effect on survival in elderly men
OR of low TT for all-cause mortality, 0.93 (95% CI, 0.87-0.99) Mean baseline serum testosterone concentration was ∼14% higher (P<.024) in men who were alive at the end of the follow-up period compared with the deceased men
Low 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<.002) HR of low BT for all-cause mortality, 1.50 (P<.001) HR of low TT for CV mortality, 1.38 (95% CI, 1.02-1.85) HR of low BT for CV mortality, 1.36 (95% CI, 1.04-1.79)
Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European Prospective Investigation Into Cancer in Norfolk (EPIC-Norfolk) prospective population study.
2007 (European Prospective Investigation Into Cancer in Norfolk)
TT
11,606
40-79/67.3
7
Population-based, Europe
Low 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<.001) OR of low TT for CV mortality, 0.53 (P<.01)
In a cohort of elderly men, DHT and calculated free DHT were associated with incident CVD and all-cause mortality
In models adjusted for cardiovascular risk factors, TT and FT were not associated with incident CVD or all-cause mortality, whereas DHT and calculated free DHT had curvilinear associations with incident CVD (P<.002 and P=.04, respectively) and all-cause mortality (P<.001 for both)
Studies documenting a positive association between endogenous testosterone and mortality
None identified
a ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; BT = bioavailable testosterone; CAD = coronary artery disease; CHD = coronary heart disease; CVD = cardiovascular disease; DHT = dihydrotestosterone; ESRD = end-stage renal disease; FT = free testosterone; HD = hemodialysis; HR = hazard ratio; LH = luteinizing hormone; MACE = major adverse cardiovascular events; MI = myocardial infarction; 25(OH)D = 25-hydroxyvitamin D; OR = odds ratio; PWV = pulse wave velocity; SHBG = sex hormone–binding globulin; TRT = testosterone replacement therapy; TT = total testosterone.
An assessment of correlations between endogenous sex hormone levels and the extensiveness of coronary heart disease and the ejection fraction of the left ventricle in males.
After adjustment for cardiovascular risk factors, a J-shaped association between plasma TT and IAD risk was found (P<.01) The HRs associated with the lowest and the highest TT quintiles relative to the second quintile were 2.23 (95% CI, 1.02-4.88) and 3.61 (95% CI, 1.55-8.45), respectively
Additional analysis for CHD had similar results (HR, 3.11 [95% CI, 1.27-7.63] and 4.75 [95% CI, 1.75-12.92], respectively) Similar J-shaped association was observed between BT and IAD risk (P=.01) No significant association of estradiol and SHBG with IAD was found
Studies documenting no association between testosterone levels and incident CAD
Cardiovascular disease included CAD, myocardial infarction, angina pectoris, coronary insufficiency, death from CAD, stroke, transient ischemic attack, congestive heart failure, and peripheral vascular disease.
(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 Patients did not undergo cardiac catheterization
Studies documenting an association between high serum concentrations of testosterone and incident CAD
None identified
a BT = bioavailable testosterone; CAD = coronary artery disease; CCS = case-control study; CHD = coronary heart disease; CS = cohort study; ECG = electrocardiography; FAI = free androgen index; FT = free testosterone; H&P = history and physical examination; HR = hazard ratio; IAD = ischemic arterial disease; PCS = prospective cohort study; SHBG = sex hormone–binding globulin; TT = total testosterone.
b Cardiovascular events included stroke, CAD, sudden cardiac death, and peripheral arterial disease.
c Cardiovascular disease included CAD, myocardial infarction, angina pectoris, coronary insufficiency, death from CAD, stroke, transient ischemic attack, congestive heart failure, and peripheral vascular disease.
An assessment of correlations between endogenous sex hormone levels and the extensiveness of coronary heart disease and the ejection fraction of the left ventricle in males.
Authors visually estimated the maximum percent reduction in luminal diameter of the left main, left anterior descending, left circumflex, and right coronary arteries. The mean of these 4 values was used to estimate CAD severity.
Inverse correlation between TT and FT levels and CAD severity
Coronary artery score: authors multiplied the degree of coronary artery obstruction by the number of stenoses.
Inverse correlation between TT and CAD severity
r=−0.52, P<.01
Positive correlation
None identified
a CAD = coronary artery disease; CCS = case-control study; FAI = free androgen index; FT = free testosterone; TT = total testosterone.
b Duke prognostic coronary artery index: a prognostic tool involving the extent and severity of atherosclerotic lesions in coronary arteries.
c Genisi score: Calculation based on location and number of stenotic coronary artery segments and degree of luminal narrowing.
d Authors visually estimated the maximum percent reduction in luminal diameter of the left main, left anterior descending, left circumflex, and right coronary arteries. The mean of these 4 values was used to estimate CAD severity.
e Coronary artery score: authors multiplied the degree of coronary artery obstruction by the number of stenoses.
Free testosterone plasma levels are negatively associated with the intima-media thickness of the common carotid artery in overweight and obese glucose-tolerant young adult men.
FT was inversely associated with carotid artery IMT Free testosterone was inversely associated with carotid artery plaque score Carotid artery IMT and plaque score were significantly higher in patients with lower levels of FT
FT was inversely associated with mean progression of carotid artery IMT independent of age FT was inversely associated with mean progression of carotid artery IMT after adjustment for cardiovascular risk factors
Analyses with and without adjustment for cardiovascular risk factors revealed that carotid IMT was inversely and significantly correlated with TT and bioavailable testosterone levels but not with SHBG and estradiol levels
After adjustment for age, smoking, physical activity, blood pressure, and lipid levels, TT was inversely associated with carotid artery IMT The association between TT and carotid artery IMT was not independent of BMI There was no association between FT and carotid artery IMT
A multivariate model adjusted for age, BMI, mean arterial pressure, and treatment for hypertension revealed a significant association between FT and carotid artery IMT Even after adjustment for other clinically relevant factors, the significant association between FT and carotid artery IMT was not attenuated After adjustment for all other clinically relevant factors, both univariate and multivariate models ascertained the stepwise association that an FT level of ≤10.0 pg/mL was significantly associated with carotid artery IMT
After adjustment for age, systolic blood pressure, smoking, and use of lipid-lowering medications, TT was inversely associated with total carotid plaque area SHBG was not associated with changes in carotid artery IMT or plaque area
Positive correlation
None identified
a BMI = body mass index; CCS = case-control study; CS = cross-sectional study; FT = free testosterone; IMT = intima-media thickness; SHBG = sex hormone–binding globulin; TT = total testosterone.
b Cardiovascular risk factors included body mass index, waist-to-hip ratio, hypertension, diabetes, smoking, and serum cholesterol levels.
North American AA2500 T Gel Study Group AA2500 testosterone gel normalizes androgen levels in aging males with improvements in body composition and sexual function.
Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study.
North American AA2500 T Gel Study Group AA2500 testosterone gel normalizes androgen levels in aging males with improvements in body composition and sexual function.
Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes.
Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study.
Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes.
Fifty-two-week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone.
Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study.
Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study.
In patients with low levels of baseline testosterone, exogenous testosterone did not affect any of the lipid subfractions In patients with normal levels of baseline testosterone, exogenous testosterone resulted in a significant decrease in total cholesterol levels In patients with normal levels of baseline testosterone, exogenous testosterone did not affect the levels of LDL, HDL, or triglyceride levels In patients with chronic disease or in those on glucocorticoid therapy, exogenous testosterone resulted in a small decrease in levels of HDL In patients with chronic disease or in those on glucocorticoid therapy, exogenous testosterone did not affect the levels of total cholesterol, LDL, or triglycerides
Exogenous testosterone resulted in reduced levels of total cholesterol The improvement in total cholesterol was more significant for patients with reduced levels of baseline testosterone No significant change in total cholesterol in patients with baseline testosterone of >10 nmol/L Exogenous testosterone did not affect levels of LDL or HDL The effect of testosterone replacement therapy on triglyceride levels was not examined in this meta-analysis
Exogenous testosterone resulted in small but significant reduction in the levels of total cholesterol, LDL, and HDL Exogenous testosterone did not affect triglyceride levels
Fifty-two-week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone.
Heufelder et al34 administered testosterone gel, 50 mg TD, for 52 wk.
16 Hypogonadal men with T2DM
HOMA-IR, HbA1c, fasting plasma glucose
HOMA-IR decreased by 4.2 in TRT group (P<.001) HbA1c decreased by about 1% after 13 wk in TRT group (P<.001) HbA1c decreased by about 1.5% after 52 wk in TRT group (P<.001) Fasting plasma glucose decreased by 1.9 mmol/L in TRT group (P=.062)
Jones et al32 administered testosterone 2% gel, 3-g metered dose (60 mg testosterone), for 12 mo.
220 Hypogonadal men with T2DM and/or MetS
HOMA-IR, HbA1c, body composition
HOMA-IR decreased by 15.2% after 6 mo with TRT (P=.018) HOMA-IR decreased by 16.4% after 12 mo with TRT (P=.006) HbA1c decreased by 0.44% after 9 mo with TRT (P=.035)
Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study.
Kalinchenko et al145 administered testosterone undecanoate, 1000 mg IM, given at baseline and after 6 and 18 wk.
113 Hypogonadal men with MetS
HOMA-IR, fasting plasma glucose, BMI, WC, waist-to-hip ratio
HOMA-IR decreased by 1.49 in TRT group (overall P=.04) No significant change in fasting plasma glucose in TRT group Significant reduction in BMI, weight, waist-to-hip ratio, hip circumference, and WC in TRT group (P<.001 for all except for waist-to-hip ratio; P=.04 for waist-to-hip ratio)
Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes.
Kapoor et al143 administered testosterone, 200 mg IM once every 2 wk for 3 mo.
24 Hypogonadal men with T2DM
HOMA-IR, HgA1c, fasting plasma glucose
HOMA-IR decreased by 1.73 in TRT group (P=.02) HgA1c decreased by 0.37% in TRT group (P=.03) Fasting plasma glucose decreased by 1.58 mmol/L in TRT group (P=.03)
Malkin et al150 administered Sustanon 250 (testosterone propionate 30 mg, testosterone phenylpropionate 60 mg, testosterone isocaproate 60 mg, and testosterone decanoate 100 mg/mL) IM injection. Two IM injections were given 2 wk apart.
13 Men with CHF and no T2DM
HOMA-IR, fasting plasma glucose, glucose tolerance, body composition
HOMA-IR decreased by 1.9 in TRT (P=.03) Fasting plasma glucose decreased by 0.61 mmol/L in TRT (P=.03) Total body mass increased by 1.5 kg in TRT (P=.008) Percent body fat decreased by 0.8% in TRT (P=.02)
Studies documenting a detrimental effect of testosterone therapy on indices of glycemic control
None identified
a BMI = body mass index; CHF = congestive heart failure; DBPCC = double-blind placebo-controlled crossover study; DBRCT = double-blind randomized controlled trial; HgA1c = hemoglobin A1c; HOMA-IR = homeostatic model of insulin resistance; IM = intramuscular; MetS = metabolic syndrome; SBPCC = single-blind placebo-controlled crossover study; SBRCT = single-blind randomized controlled trial; T2DM = type 2 diabetes mellitus; T = transdermal; TG = triglycerides; TRT = testosterone replacement therapy; WC = waist circumference.
Fifty-two-week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone.
Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study.
Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes.
administered Sustanon 250 (testosterone propionate 30 mg, testosterone phenylpropionate 60 mg, testosterone isocaproate 60 mg, and testosterone decanoate 100 mg/mL) IM injection. Two IM injections were given 2 wk apart.
Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study.
Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study.
Singh et al155 study: group 1 (n=12) received testosterone enanthate, 25 mg IM weekly; group 2 (n=12) received testosterone enanthate, 50 mg IM weekly; group 3 (n=12) received testosterone enanthate, 125 mg IM weekly; group 4 (n=11) received testosterone enanthate, 300 mg IM weekly; and group 5 (n=14) received testosterone enanthate, 600 mg IM weekly.
No significant correlation between endogenous testosterone levels and levels of CRP No change in CRP levels with T therapy, regardless of the testosterone dose
Studies documenting negative effect of testosterone therapy on markers of inflammation
study: group 1 (n=12) received testosterone enanthate, 25 mg IM weekly; group 2 (n=12) received testosterone enanthate, 50 mg IM weekly; group 3 (n=12) received testosterone enanthate, 125 mg IM weekly; group 4 (n=11) received testosterone enanthate, 300 mg IM weekly; and group 5 (n=14) received testosterone enanthate, 600 mg IM weekly.
Testosterone and cardiovascular risk summary assessments
Evidence level
Low levels of total, bioavailable, and free testosterone are associated with increased risk of mortality from all causes and CV disease
IIa
Incident CAD is associated with lower levels of total, bioavailable, or free testosterone
IIa
Severity of CAD is inversely correlated with serum concentrations of total, bioavailable, or free testosterone
IIa
The available evidence is insufficient to conclude whether there exists a relationship between ischemic stroke and serum androgens
NA
Carotid intima-media thickness and/or carotid plaque volume are inversely correlated with serum concentrations of total, bioavailable, or free testosterone
IIa
Testosterone therapy is associated with a significant reduction in obesity and fat mass
Ib
Testosterone therapy is associated with small decreases in serum concentrations of total cholesterol, HDL, and LDL. No clear effect on triglycerides has been documented
IIa
Testosterone therapy is associated with a decrease in serum glucose concentrations, HbA1c, and insulin resistance in diabetic and prediabetic men
Ia
Testosterone therapy is associated with an inconsistent reduction in serum concentrations of inflammatory markers
Ib
Testosterone therapy improves time to onset of symptomatic angina with exercise
Ib
Testosterone therapy improves exercise capacity and peak oxygen consumption in men with symptomatic congestive heart failure as defined by NYHA functional class II
Ia
CAD = coronary artery disease; CV = cardiovascular; HbA1c = hemoglobin A1c; HDL = high-density lipoprotein cholesterol; LDL = low-density lipoprotein cholesterol; NA = not available; NYHA = New York Heart Association.
studied 1031 men in the Veterans Administration health care system with serum T levels of less than 250 ng/dL. The mean age was 62 years, and mean follow-up was 40.5 months. Mortality in T-treated men was reduced by half in treated men compared with untreated men, at 10.3% vs 20.7%, respectively (P=.0001). Multivariate adjustment for age, body mass index, T level, medical morbidity, diabetes, and coronary heart disease yielded a hazard ratio (HR) of 0.61 (95% CI, 0.42-0.88; P=.008), indicating significant reduction in mortality with T therapy.
investigated a group of 581 diabetic men followed for a mean of 5.8 years. Men with low levels of serum T, defined as a serum T level of less than 10.4 nmol/L (300 ng/dL), had increased mortality compared with men with T values above this threshold. Adjusted mortality in the low T group was 17.2% compared with 9.0% in the normal T group (P=.003). In these populations, the multivariate-adjusted HR for decreased survival was 2.02 (95% CI, 1.2-3.4; P=.009). Untreated men with low T concentrations had mortality of 19.2%, compared with treated men, in whom mortality was again reduced by approximately half, at 8.4%. Notably, this value approximated the mortality in men with normal serum T concentrations. After multivariate adjustment, the HR for decreased survival in the untreated group was 2.3 (95% CI, 1.3-3.9; P=.004).
studied 25,420 US Medicare recipients aged 65 years and older. In this study, a cohort of 6355 men treated with at least 1 injection of T between January 1, 1997, and December 31, 2005, were matched to 19,065 T nonusers at a 1:3 ratio based on a composite MI prognostic score. A significant trend toward reduced MI rates with T administration was noted with increasing quartiles of risk.
For men in the highest prognostic MI risk quartile, treatment with T therapy was associated with significantly reduced risk (HR, 0.69; 95% CI, 0.53-0.92). Eisenberg et al
Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European Prospective Investigation Into Cancer in Norfolk (EPIC-Norfolk) prospective population study.
Association of sex steroids, gonadotrophins, and their trajectories with clinical cardiovascular disease and all-cause mortality in elderly men from the Framingham Heart Study.
Gonadal and adrenal androgen deficiencies as independent predictors of increased cardiovascular mortality in men with type II diabetes mellitus and stable coronary artery disease.
The majority have reported a significant association of low T with mortality in community cohorts as well as in populations with medical conditions, including renal disease, diabetes, erectile dysfunction, and prostate cancer treated with androgen deprivation. A meta-analysis by Araujo et al,
which investigated 16,184 community-based participants with a mean follow-up of 9.7 years, found that low T levels were associated with an increased risk of CV-related mortality with an HR of 1.35 (95% CI, 1.13-1.62; P<.001). Androgen deprivation therapy has also been associated with increased CV events and mortality.
Androgen deprivation therapy for prostate cancer is associated with cardiovascular morbidity and mortality: a meta-analysis of population-based observational studies.
In older men an optimal plasma testosterone is associated with reduced all-cause mortality and higher dihydrotestosterone with reduced ischemic heart disease mortality, while estradiol levels do not predict mortality.
reported that the third quartile for serum T was associated with the lowest mortality and higher mortality occurred in men in the lowest 2 quartiles as well as the highest quartile.
Summary Statement
Low levels of TT, bioavailable T, and free T are associated with increased risk of mortality from all causes and CV disease.
Level of Evidence
IIa
Testosterone and Incident CAD
Eleven studies have reported on the association of serum T concentrations and incident CAD (Table 3).
An assessment of correlations between endogenous sex hormone levels and the extensiveness of coronary heart disease and the ejection fraction of the left ventricle in males.
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