Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials

  • Lin Xu1,

    Affiliated with

    • Guy Freeman1,

      Affiliated with

      • Benjamin J Cowling1 and

        Affiliated with

        • C Mary Schooling1, 2Email author

          Affiliated with

          BMC Medicine201311:108

          DOI: 10.1186/1741-7015-11-108

          Received: 17 December 2012

          Accepted: 15 March 2013

          Published: 18 April 2013

          Abstract

          Background

          Testosterone therapy is increasingly promoted. No randomized placebo-controlled trial has been implemented to assess the effect of testosterone therapy on cardiovascular events, although very high levels of androgens are thought to promote cardiovascular disease.

          Methods

          A systematic review and meta-analysis was conducted of placebo-controlled randomized trials of testosterone therapy among men lasting 12+ weeks reporting cardiovascular-related events. We searched PubMed through the end of 2012 using “(“testosterone” or “androgen”) and trial and (“random*”)” with the selection limited to studies of men in English, supplemented by a bibliographic search of the World Health Organization trial registry. Two reviewers independently searched, selected and assessed study quality with differences resolved by consensus. Two statisticians independently abstracted and analyzed data, using random or fixed effects models, as appropriate, with inverse variance weighting.

          Results

          Of 1,882 studies identified 27 trials were eligible including 2,994, mainly older, men who experienced 180 cardiovascular-related events. Testosterone therapy increased the risk of a cardiovascular-related event (odds ratio (OR) 1.54, 95% confidence interval (CI) 1.09 to 2.18). The effect of testosterone therapy varied with source of funding (P-value for interaction 0.03), but not with baseline testosterone level (P-value for interaction 0.70). In trials not funded by the pharmaceutical industry the risk of a cardiovascular-related event on testosterone therapy was greater (OR 2.06, 95% CI 1.34 to 3.17) than in pharmaceutical industry funded trials (OR 0.89, 95% CI 0.50 to 1.60).

          Conclusions

          The effects of testosterone on cardiovascular-related events varied with source of funding. Nevertheless, overall and particularly in trials not funded by the pharmaceutical industry, exogenous testosterone increased the risk of cardiovascular-related events, with corresponding implications for the use of testosterone therapy.

          Keywords

          Testosterone Cardiovascular Men Trial

          Background

          In observational studies low serum testosterone is associated with cardiovascular disease [1, 2]. Testosterone may protect or be a secondary risk marker of other processes [13]. On the precautionary principle, expert advice and reviews, largely based on observational evidence, warn that cardiovascular disease may be increased by androgen deprivation therapy [4] and low testosterone [5, 6]. Awareness of low testosterone as a treatable condition is being raised [7, 8]. Testosterone use is increasing [911], possibly as self-medication in response to advertising.

          In 2004 the Institute of Medicine (IOM) reviewed the evidence on testosterone therapy and concluded, largely based on placebo-controlled trials, that ‘there is not clear evidence of benefit for any of the health outcomes examined’ [12]. The IOM recommended small-scale trials to establish the efficacy of testosterone therapy where other treatments were not available [12]. To our knowledge, no trial has been designed to assess the effect of testosterone therapy on cardiovascular morbidity or mortality. Previous meta-analyses of randomized placebo-controlled trials found that testosterone therapy resulted in a non-significantly higher risk of cardiovascular events, based on adverse events, but only included trials through March 2005 [13, 14]. A more recent meta-analysis included trials through August 2008 but only reported on three specific cardiovascular outcomes, that is, arrhythmia, coronary bypass surgery and myocardial infarction [15]. Given the widespread use of testosterone, the high prevalence of cardiovascular disease in older men and no comprehensive assessment of the effect of testosterone therapy on cardiovascular events, an up-to-date meta-analysis may help inform clinical practice. We carried out a meta-analysis of adverse events from randomized placebo-controlled trials to examine the overall risk of cardiovascular-related events associated with testosterone therapy.

          Methods

          This meta-analysis follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist [see Additional file 1] and a published protocol (CRD42011001815) [16]. Two reviewers (LX and CMS) independently searched for and selected trials, resolving any differences by consensus. Two statisticians (GF and BJC) extracted information from the selected trials.

          Data sources and searches

          We (LX and CMS) systematically searched PubMed until 31st December 2012 using “(“testosterone” or “androgen”) and (random*) and trial” with the selection limited to studies in men in English, because a preliminary search only found studies in English. We (LX and CMS) searched the World Health Organization (WHO) International Clinical Trials Registry Platform for any trial using testosterone as an intervention. From this search, we (LX and CMS) discarded any studies both agreed were irrelevant based on title or abstract and read the remaining. We did a bibliographic search of the selected trials and relevant reviews.

          Study selection

          We included randomized placebo-controlled trials giving cardiovascular-related events by study arm, because a report may focus on a particular aspect of the trial [17, 18] and not report all events that have occurred [1719]. We excluded trials that only gave treatment-related events in the testosterone arm because these might not include full reporting of events in the placebo arm. Initially, we intended to exclude trials that only reported withdrawals as potentially less comprehensive than reporting of adverse events [18, 19], however this turned out to be a very fine distinction, so we included any trial reporting cardiovascular-related events by study arm.

          We included any randomized controlled trial (RCT) of testosterone, but not other androgens, compared with placebo, including a comparison against a background of other treatments, because men likely to be taking testosterone may also be in treatment for other conditions. We excluded trials of less than twelve weeks’ duration to assess long-term rather than acute effects of testosterone therapy.

          We checked for duplication based on overlapping authorship, study description, number of participants and participant characteristics. When duplication occurred we used the study with the most comprehensive description of adverse events.

          Outcome

          The primary outcome was composite cardiovascular-related events; because we anticipated too few events for robust assessment by cardiovascular event type; and a system-wide composite outcome may be most suitable for adverse events [20]. Cardiovascular-related events were defined as anything reported as such by the authors, that is, events reported as cardiac disorders, cardiovascular complaints, cardiovascular events, vascular disorders, cardiac or cardiovascular, or where the event description fell within the International Statistical Classification of Disease (ICD) version 10 chapter IX (I00 to I99). Most trials only reported serious adverse events, but a few also reported a wider range of events, so we also examined the effect of testosterone therapy by seriousness. Seriousness was based on the US Department of Agriculture definition of serious adverse events and the type of cardiovascular event generally considered serious [21]. Serious cardiovascular events were defined as cardiovascular-related events which the authors described as serious adverse events or where the outcome was death, life-threatening, hospitalization, involved permanent damage or required medical/surgical intervention, or was one of the following types of cardiovascular event: myocardial infarction, unstable angina, coronary revascularization, coronary artery disease, arrhythmias, transient ischemic attacks, stroke or congestive heart failure but not deep vein thrombosis.

          Data extraction and quality assessment

          A statistician (GF) extracted the number of participants randomized and cardiovascular-related events by trial arm. Event classification was checked by a physician (LX). A second statistician (BJC) checked the information extracted. Where trials reported cardiovascular-related events without giving the study arm, we contacted the authors twice by email to ask for cardiovascular-related events by study arm.

          The reviewers (LX and CMS) independently used an established tool to evaluate the quality of each trial [22], focusing on the quality of reporting of cardiovascular-related adverse events. First, we reported whether cardiovascular-related events were individually listed in a table by study arm, because these are easier to identify unambiguously. Second, we reported whether the type and severity of cardiovascular-related events reported was either pre-specified or identified before the allocation was revealed, because issues have been expressed about the reporting of adverse events [23, 24]. Cardiovascular-related events vary in severity making the selection criteria and categorization crucial to an outcome assessed from adverse events.

          Sensitivity analysis

          We initially planned only to assess whether the effects of testosterone on cardiovascular-related events varied with average baseline testosterone, because we did not expect sufficient trials for sub-group analysis by type of testosterone product or by type of cardiovascular-related event. However, the reporting of adverse events may be open to interpretation [23], and may not be comprehensive [25]. Given potential lack of clarity as to the selection of the cardiovascular-related adverse events reported, we also examined whether the effect of testosterone therapy varied with funding source. Finally, we also considered cardiovascular-related death as an outcome.

          Data synthesis and analysis

          We used the number of participants randomized as the denominator and included all cardiovascular-related events from the start. We used funnel plots and ‘trim and fill’ to assess publication bias, that is, missing trials. We used I2 to assess heterogeneity between trials, using fixed effects models where there was low heterogeneity (I2 <30%), otherwise using random effects models. We obtained the pooled odds ratio, using the ‘metabin’ function of the ‘meta’ package in R 2.14.1 (R Development Core Team, Vienna, Austria). We used meta-analysis regression, with inverse variance weighting, to assess whether the effects of testosterone therapy varied with baseline testosterone or funding source, using the ‘rma’ function of the ‘metafor’ package in R 2.14.1. Initial analysis showed the pooled odds ratio was similar using a Peto or a Mantel-Haenszel estimate; we used inverse variance weighting for consistency with the meta-regression.

          This study is an analysis of published data, which does not require ethics committee approval.

          Results

          The initial search yielded 1,882 papers, of which 169 were selected for full text scrutiny. Of these 169 papers, 31 concerned different placebo-controlled randomized trials among men of testosterone therapy of 12+ weeks reporting cardiovascular-related events by study arm. We found one additional recent trial from the WHO International Clinical Trials Registry Platform [26]. We did not find any additional such trials from a bibliographic search of these 32 papers or from eight reviews [2734]. Two additional trials [35, 36] selected for full text scrutiny had cardiovascular-related events shown in a plot from one previous meta-analysis [13], but not the other meta-analyses [14, 15] or in the relevant publications [3537]. The search did not find one small non-randomized trial [38] included in two previous meta-analyses [13, 15]. The search found one additional trial [39] potentially relevant to the earlier meta-analyses [13, 14], two additional trials [40, 41] potentially relevant to the most recent meta-analysis [15] and 11 subsequent trials. We sought clarification concerning events by study arm for 10 trials as set out in Additional file 2. Six authors never responded [37, 40, 4245], three responded but did not provide any relevant information [36, 46, 47] and one provided information [48]. We included this later trial [48], one of the others that gave cardiovascular deaths, but not other cardiovascular-related events, by study arm [46] and one that gave vascular events, but not all cardiovascular-related events by study arm [44]. Figure 1 shows the search strategy resulting in 27 placebo-controlled randomized trials.
          http://static-content.springer.com/image/art%3A10.1186%2F1741-7015-11-108/MediaObjects/12916_2012_758_Fig1_HTML.jpg
          Figure 1

          Selection process for the placebo-controlled randomized trials of the effects of testosterone therapy on cardiovascular-related events.

          Table 1 shows the 27 trials over 25 years of 2,994 mostly middle-aged or older men (1,733 testosterone and 1,261 placebo) with low testosterone and/or chronic diseases, who experienced 180 cardiovascular-related events. Most of the trials were in Western settings. Thirteen trials were supported by the pharmaceutical industry. Two trials were stopped early [49, 50], one because of adverse events among the men allocated to testosterone [50] and one because ‘it would not be feasible to demonstrate - in the foreseeable future - a beneficial effect of testosterone [on mortality] by continuing the study’ [49].
          Table 1

          Characteristics of placebo-controlled randomized trials giving the effects of testosterone therapy on cardiovascular-related events among men

          Author and publication year

          Study

          Participants

          Industry funding

           

          Setting

          Duration

          Dose

          Cardiovascular-related events based on

          Age range

          Number

          Health status

          Initial T (nmol/L)

           

          Copenhagen Study Group [49] 1986

          Denmark

          About 16 monthsa

          200 mg/8 h micronized T, PO

          Deaths

          24 to 79

          221

          alcoholic cirrhosis

          about 20

          None given

          Marin [39] 1993

          Denmark

          9 months

          T gel 125 mg/day

          Withdrawals

          40 to 65

          21

          Obese, low T

          15.3

          Funded by Besins Iscovesco

          Hall [51] 1996

          UK

          9 months

          T enanthate 250 mg /month, IM

          Withdrawals

          34 to 79

          35

          Rheumatoid arthritis

          16.1

          Funded by Schering Healthcare

          Sih [52] 1997

          US

          12 weeks

          T cypionate IM every 14 to 17 days

          Withdrawals

          51 to 79

          32

          T<60 ng/dl

          9.2

          None given

          English [53] 2000

          UK

          12 weeks

          Transdermal T 5 mg/day

          Withdrawals and safety data

          Mean 62

          50

          Coronary artery disease

          12.9

          Patches given by Smith Kline Beecham

          Snyder [19] 2001

          US

          36 months

          Transdermal T 6 mg/day

          Clinically apparent from hospital records

          65+

          108

          Men with T one SD <475 ng/dl

          12.7

          Patches given by ALZA Corporation

          Amory [54] 2004

          US

          36 months

          T enanthate 200 mg/2 weeks, IM

          Serious adverse cardiovascular events

          65 to 83

          48

          TT <350 ng/dl

          10

          None given

          Kenny [55] 2004

          US

          12 weeks

          T enanthate 200 mg/3 weeks, IM

          General description

          73 to 87

          11

          Cognitive decline, bioavailable T <128 ng/dl

          14.1

          None

          Svartberg [56] 2004

          Norway

          26 weeks

          T enanthate 250 mg/month, IM

          General description

          Mean 66

          29

          COPD

          21.1

          None

          Brockenbrough [57] 2006

          US

          6 months

          Transdermal T gel 10 g/day

          Side effects and adverse events

          Mean 56

          40

          Dialysis and TT <300 ng/dl

          7.3

          Supported by Auxilium Pharmaceuticals

          Malkin [58] 2006

          UK

          12 months

          Transdermal T patch 5 mg/day

          Serious adverse events

          Mean 64

          76

          Heart failure

          13.0

          Medication given by Watson Pharmaceuticals

          Merza [59] 2006

          UK

          6 months

          Transdermal T patch 5 mg/day

          Withdrawals

          40+

          39

          TT <10 nmol/L

          8.0

          Supported by Ferring Pharmaceuticals Ltd

          Nair [60] 2006

          US

          24 months

          Transdermal T patch 5 mg/day

          Adverse events

          60+

          62

          DHEA<1.57 μg/ml, bioavailable T <103 ng/dl

          13.7

          Supported by The Endocrine Society

          Emmelot-Vonk [61] 2008

          Netherlands

          6 months

          TU 160 mg/day, PO

          Adverse events

          60 to 80

          237

          TT<13.7 nmol/L

          10.7

          Medication given by Organon NV

          Svartberg [41] 2008

          Norway

          52 weeks

          TU 1000 mg, MI at 0, 6, 16, 28 and 40 weeks

          Deaths

          60 to 80

          38

          TT≤11.0 nmol/L

          8.3

          Grant from Bayer Schering Pharma AG

          Caminiti [62] 2009

          Italy

          12 weeks

          TU 1000 mg MI for 0, 6 and 12 weeks

          General description of events

          66 to 76

          70

          Heart failure

          7.0

          None given

          Chapman [48] 2009

          Australia

          1 year

          TU 80 mg orally twice a day

          Hospitalizations

          65+

          23

          Undernourished

          18.8

          Organon provided funding

          Legros [46] 2009

          Europe

          1 year

          TU 80, 160 and 240 mg orally per day

          Safety assessments

          50+

          316

          Free T<0.26 nmol/L

          12.8

          Funded by Schering-Plough

          Aversa [63] 2010

          Italy

          24 months

          TU 1,000 mg (every 12 weeks)

          Safety aspects

          45 to 65

          50

          MS and/or T2DM TT<3.0 ng/ml

          8.5

          None given

          Basaria [50] 2010

          US

          About 6 monthsa

          Transdermal T gel 100 mg/day

          Cardiovascular-related events

          65+

          209

          Frial, TT 100 to 350 ng/dl

          8.4

          Medication given by Auxilium Pharmaceuticals

          Srinivas-Shankar [64] 2010

          US

          6 months

          Transdermal T gel 50 mg/day

          Serious adverse events and withdrawals

          65+

          274

          TT≤12 nmol/L (345 ng/dl)

          11.0

          Supported by Bayer Schering Pharma

          Jones [65] 2011

          Europe

          12 months

          T gel 60 mg/day

          Cardiovascular events

          37 to 88

          220

          Hypogonadal with type 2 diabetes and/or MetS,

          9.4

          Supported by ProStrakan

          Ho 2011 [66]

          Malaysia

          1 year

          TU 1000 mg MI for 0, 6, 18, 30 and 42 weeks

          Withdrawals

          40+

          120

          T<12 nmol/L,

          9.0

          Supported by Bayer Schering Pharma

          Kaufman [44] 2011

          US

          182 days

          1.62% T gel 2.5 mg/day

          Safety aspects

          45 to 64

          274

          Hypogonadal, T<300 ng/dl

          9.8

          Funded by Abbott.

          Kalinchenko [67] 2010

          Russia

          30 weeks

          TU 1,000 mg MI for 0, 6, 18 and 30 weeks

          Withdrawal

          35 to 70

          184

          T<350 ng/dl

          7.0

          Supported by Bayer Schering Pharma

          Hoyos [68] 2012

          Australia

          18 weeks

          TU 1000 mg MI at 0, 6 and 12 weeks

          Adverse events

          18+, mean 49

          67

          Obese men with obstructive sleep apnea

          13.3

          Supported by Bayer Schering Pharma

          Spitzer [26] 2012

          US

          14 weeks

          1% T gel 10 g/day

          Adverse events

          40 to 70

          140

          Erectile dysfunction low T and a sexual partner

          12.3

          none

          atrial stopped early so duration varies. IM= intramuscularly; P, placebo; PO, orally; T= testosterone; TT= total testosterone; TU= testosterone undecanoate.

          Quality assessment

          The quality assessment (see Additional file 3) shows that two trials provided a table with a comprehensive list of cardiovascular-related events by study arm and eight trials provided a summary table of cardiovascular-related events by study arm. For 17 trials cardiovascular-related events were surmised from withdrawals and/or adverse events as given in Additional file 4, including one where the cardiovascular-related events were surmised from a P-value [65]. The type and severity of adverse events to be reported was pre-specified in one trial [61]. In the two trials terminated early the adverse events motivated termination and were identified before treatment allocation was known [49, 50]. Otherwise it was sometimes unclear whether the definition or classification was made by masked assessors.

          Data synthesis

          The funnel plot (Figure 2) shows several small studies (on the left hand side) where testosterone reduced cardiovascular-related events, however, there were no similar small studies where testosterone increased cardiovascular-related events. The forest plot (Figure 3) shows that the trials were homogeneous (I2 = 7.8%). Testosterone increased the risk of a cardiovascular-related event in a fixed effect model, odds ratio (OR) 1.54, 95% confidence interval (CI) 1.09 to 2.18. Trim and fill revised the OR to 1.69 (95% CI 1.21 to 2.38). When the analysis was restricted to serious events, whose categorization is shown in Additional file 4, the estimate was very similar (OR 1.61 (95% CI 1.01 to 2.56)) and was revised to 2.01 (95% CI 1.30 to 3.14) by trim and fill.
          http://static-content.springer.com/image/art%3A10.1186%2F1741-7015-11-108/MediaObjects/12916_2012_758_Fig2_HTML.jpg
          Figure 2

          Funnel plot of placebo-controlled randomized trials examining the effects of testosterone therapy on cardiovascular-related events.

          http://static-content.springer.com/image/art%3A10.1186%2F1741-7015-11-108/MediaObjects/12916_2012_758_Fig3_HTML.jpg
          Figure 3

          Forest plots of placebo-controlled randomized trials examining the pooled effect of testosterone therapy on cardiovascular-related events.

          Sensitivity analysis

          The cardiovascular-related event rate was lower in trials funded by the pharmaceutical industry (4% (66/1,651)) than in other trials (8% (114/1,343)). In a meta-regression model, risk of cardiovascular-related events on testosterone therapy varied with the source of funding (P-value for interaction 0.03) but not with baseline testosterone (P-value for interaction 0.70). In trials funded by the pharmaceutical industry testosterone had no effect on cardiovascular-related events, but in the other trials testosterone therapy substantially increased the risk of a cardiovascular-related event (Figure 4). Finally, 33 cardiovascular-related deaths were identified (22 testosterone arm and 11 placebo arm), for which the odds ratio was similar 1.42 (95% CI 0.70 to 2.89) to the estimate for all cardiovascular-related events, and was revised to 1.57 (95% CI 0.78 to 3.13) by trim and fill.
          http://static-content.springer.com/image/art%3A10.1186%2F1741-7015-11-108/MediaObjects/12916_2012_758_Fig4_HTML.jpg
          Figure 4

          Forest plots of placebo-controlled randomized trials examining the pooled effects of testosterone therapy on cardiovascular-related events by source of funding: upper panel funded by the pharmaceutical industry and lower panel not funded by the pharmaceutical industry.

          Discussion

          This updated meta-analysis of placebo-controlled randomized trials, with a much larger number of participants than previous meta-analyses [1315], adds to the previous findings by showing that testosterone therapy increases cardiovascular-related events among men. The risk of testosterone therapy was particularly marked in trials not funded by the pharmaceutical industry. The risks of cardiovascular-related events were similar by baseline testosterone.

          Several possible explanations exist for our findings. First, not all trials of testosterone therapy reported all cardiovascular-related events by study arm [36, 46]. Trials favoring testosterone may be unpublished. However, the funnel plot (Figure 2) and ‘trim and fill’ suggested trials favoring the placebo may be missing. Second, endogenous and exogenous testosterone may have different effects, with endogenous testosterone being protective, consistent with the observational evidence [1, 2] and with testosterone declining with age when cardiovascular disease increases with age. However, a recent Mendelian randomization study, using genetic variants as an instrumental variable for endogenous testosterone, did not corroborate protective effects of endogenous testosterone on cardiovascular disease risk factors [69]. Another possibility is that serum testosterone is not a good indicator of androgen activity [70], as has long been suggested [71] and recently substantiated by the effective use of anti-androgens in prostate cancer at castrate levels of serum testosterone [72, 73]. Third, endogenous testosterone may be beneficial, but other metabolites of exogenous testosterone, raised by testosterone therapy, such as estrogens or dihydrotestosterone, could mediate cardiovascular-related events. Exogenous estrogens do not protect men against cardiovascular disease [74]. However, higher free testosterone rather than higher estradiol appeared to mediate the cardiovascular events in a recent trial of testosterone therapy [75]. Few trials have examined the effects of dihydrotestosterone administration and have usually focused on prostate rather than cardiovascular effects [7678]. The interplay of testosterone and dihydrotestosterone is complex and challenging to disentangle in RCTs [79]. Nevertheless, exogenous testosterone lowers HDL-cholesterol [15] and raises hemoglobin, hematocrit and thromboxane [15, 80], all of which might contribute to cardiovascular disease. Thromboxane promotes clotting and blood vessel constriction. Natural experiments suggest that lower lifetime endogenous androgens are associated with a relatively lower risk of death from ischemic heart disease, based on legally castrated men [81] and men with Klinefelter’s syndrome [82]. Similarly, a meta-analysis of RCTs of androgen deprivation therapy found a non-significantly lower risk of cardiovascular mortality among men allocated to androgen deprivation [83], despite bias to the null by the competing risk of death from prostate cancer.

          Our findings are consistent with the three previous meta-analyses [1315], which all indicated a non-significantly higher risk of testosterone therapy for a composite cardiovascular outcome of the events considered, despite discrepancies in some studies [13, 14]. This meta-analysis based on many more trials (27), many more men (2,994) and correspondingly more events (180) produced a similar, but more precise estimate, with the confidence interval no longer including no effect. The difference between the estimates by funding source is consistent with other observations [84, 85] and could be due to different reporting of adverse events in industry funded trials. Differences by funding source could also be due to differences between trials. Industry funded trials reported fewer cardiovascular-related events, which reduces power although it should not affect the direction of effect. Industry funded trials tended to be in younger men. It is possible, although unusual, for the effects of treatment to be ‘crossed’ by age [86].

          From a clinical perspective the issue is ensuring that the benefits of testosterone therapy outweigh the potential risks. Almost a decade after the IOM’s report [12] the efficacy of testosterone therapy for health outcomes where treatments are not already available remains uncertain. Testosterone compared to placebo could be beneficial for glucose metabolism [65], depression [87, 88], sexual dysfunction [26, 89], bone density [90] and HIV wasting syndrome [91, 92], although whether testosterone is better than established treatments for these conditions has not been clearly established. Cardiovascular disease is common in typical users of testosterone therapy, that is, older men. The 10-year risk of a cardiovascular event for US men aged 65 to 69 years is about 28% [93]. Assuming the increased risk of cardiovascular-related events seen here with testosterone therapy would give a number needed to harm of at most 90 per year of testosterone therapy. As such, further research might focus on obtaining evidence without interventions, for example by confirming that the observed negative associations of serum testosterone with specific cardiovascular diseases extends to other androgen biomarkers, such as androgen glucuronides [94], and to other study designs less open to biases, such as Mendelian randomization. Moreover, a gene in the steroidogenesis pathway (CYP17A1) is reliably associated with coronary artery disease [95]. Establishing if CYP17A1 acts, if at all, by raising or lowering androgens would also bring clarity. Finally, consideration could be given to whether further trials should be of agents that raise or lower testosterone.

          Strengths and limitations

          Despite providing a meta-analysis of all known placebo-controlled randomized trials, limitations exist. First, the reporting of adverse events may be open to conflicts of interest [24]. The funnel plot and analysis by funding source are consistent with that possibility. A very large market is at stake [9]. Second, in a trial of a therapy, such as testosterone, which may change how men feel or their sex drive, some accidental unmasking may have occurred. Few trials assessed or reported this possibility. Third, some men in the testosterone arm stopped treatment because of increased prostate specific antigen or polycythemia, which would bias towards the null. Fourth, RCTs are not always tagged as such and could be missed [96]. However, we searched broadly and found several potentially eligible trials that had not been included in previous meta-analyses. Fifth, our study cannot include on-going trials, such as the Testosterone Supplementation and Exercise in Elderly Men trial (NCT00112151) and The Testosterone Trial (NCT00799617). However, these trials are not designed to assess the effect of testosterone on cardiovascular events and will take time to complete. If new trials show testosterone therapy to be strongly protective against cardiovascular disease, it would be against the general run of evidence to date making interpretation uncertain because of heterogeneity [97]. Sixth, the abstractors were not blinded. Seventh, most trials only reported fairly serious cardiovascular-related events, but the severity varied between trials, although for RCTs the reporting of events should be comparable within trials, and the events reported are more or less severe symptoms of cardiovascular disease on the pathway to cardiovascular mortality. An analysis restricted to events which could be identified as serious gave a similar estimate, but was limited by relying on events the authors had chosen to describe in detail by study arm and was revised upwards by trim and fill. Arguably, the standard definitions of event seriousness, including hospitalization, do not apply to frail older men, because they may be particularly prone to hospitalization. On the other hand, frail older people may also be most affected by any decrement to their already poor health, so hospitalization may represent a particularly significant event. Notably, an estimate based solely on deaths also had a similar point estimate, although the confidence interval included no effect because of low power. Eighth, two larger trials were terminated early [49, 50] which reduces power and could affect the estimates. However, the terminations took place towards the end of the planned trials and did not specifically concern cardiovascular-related events. Nevertheless, early terminations may have slightly increased the estimate and widened the confidence intervals. However, the interpretation would, most likely, have been similar. Ninth, although meta-analyses are a mainstay of evidence-based medicine they may be less reliable than large RCTs. Meta-analysis may overstate the benefits of treatment [98] however, they are less prone to overstate the harms [98]. Subsequent large RCTs rarely reverse the direction of effect from meta-analysis [99]. Tenth, given the lack of detailed cardiovascular-event reporting secondary analysis by type of cardiovascular event was not possible. Such sub-group analysis would undoubtedly be etiologically valuable. However, from a public health perspective the issue is identifying side-effects, where a composite outcome relating to a particular system (here the cardiovascular system) has been recommended [20]. Finally, the difference observed by source of funding could just be chance variation; however, testosterone therapy increased the risk of cardiovascular-related events overall.

          Conclusions

          Appropriately prescribed testosterone is undoubtedly beneficial. However, caution needs to be exercised to ensure that the associated health benefits of testosterone therapy outweigh the potential increased risk of cardiovascular-related events, particularly in older men where cardiovascular disease is common.

          Abbreviations

          CI: 

          confidence interval

          CYP17A1: 

          cytochrome P450 17A1

          IOM: 

          Institute of Medicine

          ICD: 

          International Statistical Classification of Disease

          OR: 

          odds ratio

          PRISMA: 

          Preferred Reporting Items for Systematic Reviews and Meta-Analyses

          RCT: 

          randomized controlled trial

          WHO: 

          World Health Organization. Systematic review reference number CRD42011001815.

          Declarations

          Acknowledgements

          The authors thank Steffie Woolhandler, David Himmelstein and Heidi Jones for their support.

          Authors’ Affiliations

          (1)
          School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong
          (2)
          CUNY School of Public Health at Hunter College

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