The ISSAM (International Society for Study of the Ageing Male), EAU (European Urology Association) and BSSM (British Society for Sexual Medicine Association) 1,2 suggest that a level of total testosterone (TT) of less than 8 nmol/l or free testosterone (FT) of less than 180 pmol/l in the presence of physical symptoms, require testosterone replacement therapy (TRT), however, TT of more than 12 nmol/l or FT of more than 225 pmol/l do not. Between these levels a trial of therapy for a minimum of 6 months should be considered based on symptoms 1,2 The Endocrine Society 3 recommend screening for men in high-risk groups such as diabetes, HIV and all men with erectile dysfunction (ED), considering low testosterone is as a ‘treatable’ cause of ED. This wholly appropriate detection of a previously underdiagnosed and undertreated population of men has been the major driver for the increase in testosterone prescribing over the last decade. Despite this considerable body of evidence, many reviews suggest prescribing ‘with caution’ in the elderly or only treating ‘symptomatic’ patients without adequately describing what this cautious terminology actually means. This paper attempts to clarify the benefits, risks and quality of life issues of TRT in an older population.
Evidence that low testosterone is associated with increased mortality
There is increasing evidence from multiple long-term studies that testosterone deficiency syndrome is associated with increased cardiovascular and all-cause mortality 4–13 Two recent meta-analyses have looked at a large number of long-term studies linking low testosterone to increased cardiovascular and all-cause mortality 14,15. Araujo et al.14 concluded that the evidence for a link between low testosterone and increased mortality was strong but concluded that most studies involved issues in cohort selection and choice. Haring et al. 15 looked at the data in terms of several models and found that even after strict adjustment for comorbidities there was a consistent link between mortality risk and testosterone level throughout the studies but that this did not prove causation (Table 1).
The EMAS group 4,16 recently reported 4.3 year follow-up data on 2599 men aged 40–79 and concluded that men with a baseline TT of 8 nmol/l or less and sexual symptoms had a three-fold increased mortality and a five-fold increased risk of cancer death. There authors concluded that low testosterone and ED independently predict mortality and that these men are at considerable risk of early death.
Malkin et al.17 followed up 930 men referred with coronary artery disease (CAD) for 6.9 years. The prevalence of hypogonadism was 24%, mortality rates were 21 versus 12% (P=0.002) for hypogonadal men versus eugonadal and the study was halted early at 6.9 years. Six published studies, usually involving small samples, have shown that low TT and FT is associated with CAD, and four studies have shown no association 18. Four studies have shown inverse associations between low TT or FT and the severity of CAD 18. One involved 803 men assessed by Gensini score, based on the location and number of stenotic coronary artery segments and degree of luminal narrowing 19. Such studies do not establish whether low TT or FT is a cause or a consequence of CAD.
Muraleedaran et al.20 screened a primary care diabetic population of 587 patients and followed them up for 5.8 years. They found 475 of men had normal TT levels, 22% were overtly hypogonadal (<8 nmol/l) and 31% were in the borderline range. These percentages were in close agreement with earlier publications by Kapoor et al.21 and Hackett et al.22. The mortality rate 21 over 5 years in the hypogonadal group was 17.2 versus 9% in the normal testosterone cohort.
Effect of TRT on surrogate markers for cardiovascular risk
TRT has been shown to produce modest reduction in serum total cholesterol (TC) as early as after 4 weeks 23 but most studies have reported a decrease after 3 months 23. Greater reductions were seen in obese men 23 with metabolic syndrome. The MRFIT 24 study showed that hypogonadal men had slightly increased triglycerides and decreased HDL, leading to the suggestion that TRT might be expected to lower triglycerides and increase HDL. A recently published 5-year registry involving 230 men treated with 5 years showed highly significant reductions in TC, LDL and triglycerides with increase in HDL, associated with significant reduction in weight, BMI and visceral fat 25.
The decrease in serum triglycerides follows a similar pattern: after 4 weeks with decrease over 9 months 23 and maximum effect at 12 months 25. The decrease in LDL cholesterol seems somewhat slower: after 3 months, after 40–44 weeks, or after 12 months 23
Studies have found both an increase and decrease in HDL cholesterol 26,27 dependent on the presence of diabetes or the use of statins. A decline was noted in interleukin-6 and tumour necrosis factor-α within 16 weeks 26 and in another study after 16 weeks 23. In the Moscow Study, C-reactive protein was reduced by TRT at 30 weeks versus placebo 26.
Several of the above studies have shown reduction in waist circumference, visceral fat and BMI 22,26,27. Longer term registry studies suggest considerable weight loss can be seen for up to 4 years 25. In some studies, a decline in diastolic blood pressure has been observed, after 3–9 months 25,26 and in systolic blood pressure. Maximum effects were observed after 12 months and up to 5 years 25.
A recent 5-year registry of 255 men aged 36–69 years 25 treated with long acting testosterone undecanoate has shown mean reductions in waist circumference of 8.5 cm, weight reduction of 15.5 kg, TC by 2.4 mmol/l, reduction in HDL and triglycerides with HbA1c by 0.9% (7.06–6.16).
Effects on angina threshold and heart failure
Studies have shown pharmacological doses of testosterone to relax coronary arteries when injected intraluminally 28 and to produce modest, but consistent, improvement in exercise-induced angina and reverse associated ECG changes 29. The mechanism of action is considered to be via blockade of calcium channels with an effect of similar magnitude to nifedipine 29.
In men with chronic stable angina pectoris, placebo-controlled studies show that the ischaemic threshold increased after 4 weeks of TRT and a recent study demonstrates improvement continuing beyond 12 months 28,29. Exercise capacity in men with chronic heart failure increased after 12 weeks 30, predominantly through the improvement in skeletal muscle performance, an effect likely to be important in reducing frailty in elderly men.
Lower levels of endogenous testosterone have been shown to be associated with longer duration of the QTc interval and TRT has been shown to reverse this effect 31. Carotid artery intimal thickness is associated with low endogenous testosterone and TRT significantly improved carotid intimal thickness and brachial artery flow mediated dilatation after 6 months in a randomized-controlled study 32.
Testosterone deficiency and type 2 diabetes
Diabetes specialists have traditionally considered the fall in testosterone level as being a consequence of obesity but studies now clearly show that low testosterone leads to visceral obesity, metabolic syndrome and is also a consequence of obesity 3. Large long-term studies have shown that baseline levels of testosterone predict the later development of type 2 diabetes 24,33,34. In the case of MMAS 34, a baseline TT of less than 10.4 nmol/l was associated with a greater than four-fold incidence of type 2 diabetes over the next 9 years and NHANES-III followed up men from as young as 20 and found a similar four times greater prevalence independent of obesity or ethnicity 33. There is high level evidence that TRT improves insulin resistance, as measured by HOMA-IR 35–38, reduces HbA1c35 by ∼0.7% by 18 months 39, and established inflammatory markers associated with increased cardiovascular risk (C-reactive protein, interleukin-6 and tumour necrosis factor-α) in men with type 2 diabetes and metabolic syndrome 25–27. There is also a high level of evidence for reduction in TC, weight, BMI 26–28 and visceral fat (a significant marker for cardiovascular risk) and improvement of lean muscle mass. The BLAST study studied men with low testosterone and type 2 diabetes with a mean age of 62 40,41 Results suggested that men with depression (23% of the cohort with diabetes) were markedly less responsive to testosterone and that improvement in metabolic parameters required sustained levels of testosterone above 12 nmol/l 40,41, whereas highly significant benefits in sexual function and quality of life were seen when treatment levels of over 8 nmol/l were achieved 42.
TRT, cardiovascular events and mortality
A retrospective US study involved 1031 men with 372 on TRT. The cumulative mortality was 21% in the untreated group versus 10% (P=0.001) in the treated group with the greatest effect in younger men and those with type 2 diabetes 43. A prospective UK study of 587 men with type 2 diabetes (20 involved 5.8 years follow-up). Low testosterone was defined as TT <10.4 nmol/l. Fifty-eight men were treated with testosterone for 2 years or more. The mortality rate was 20% in the untreated group, 9.1% in the normal group independent of comorbidities and therapies. Mortality was 8.6% in the treated group (P=0.049). Neither of these studies involved randomization and both were subject to selection bias.
A trial of 209 elderly frail men (the TOM study) 35 over 65 randomized to receive either placebo or topical testosterone gel was terminated early as there were 23 cardiac events (two deaths) in the 106 men in the testosterone group versus five men in the placebo group, despite positive results in study end points of frailty and mobility. These events included investigator reported ECG changes, dysrhythmias, hypertension and even ankle oedema. The active treatment group had more severe CAD. The study involved rapid escalation up to 150 mg per day, above the manufacturers recommended dose and many of the events were reported with inadequate validation. A recent retrospective US study of 8709 men 44 with baseline TT of 10.4 nmol undergoing coronary angiography involved follow-up for a mean 840 days.
In the cohort of 7486 patients not receiving testosterone therapy, 681 died, 420 had myocardial infarctions (MIs), and 486 had strokes. Among 1223 patients receiving testosterone therapy, 67 died, 23 had MIs, and 33 had strokes. At first sight these results would closely agree with the findings in the study by Muraleedaran and colleagues 20,43 suggesting a beneficial effect of TRT, but a complex statistical analysis reversed the trend and concluded that there was a greater risk in the TRT group. This paper, although widely quoted, has been heavily criticized and largely discredited for a number of valid reasons. There was little evidence of adequate treatment or effective follow-up. There were concerns that 1132 patients experiencing events were excluded because they were prescribed TRT after the event when surely these should have been included in the untreated group, increasing the events by 70%. The authors reviewed these issues and concluded that this number should have been 112 but that over a 100 women were included in error, raising serious concerns over the validity of this study. The baseline TT was 1 nmol/l lower in the treated group and previous studies show that this may increase the mortality by up to 30%, 5–13yet this was not considered in the 50 confounders for analysis. Symptoms were not considered, yet these are a key to the diagnosis of hypogonadism. Men were likely to be treated with TRT on the basis of symptoms if they suffered from ED, and the presence of ED and low testosterone have been shown to be independent risk factors, particularly in hypogonadal men, increasing cardiovascular mortality by over 50% 16,45.
Finkle et al. 46 compared nonfatal infarcts in the 3 months after commencing TRT with a cohort of men commencing phosphodiesterase type 5 inhibitors. This study has been heavily criticized as the benefits of TRT would have taken many months and that fatal events were not even recorded, despite evidence that TRT reduces fatality but not necessarily nonfatal events. There was little evidence of adequate treatment levels or follow-up in the TRT group. Recent studies suggest that phosphodiesterase type 5 inhibitors actually increase testosterone levels 47 and may reduce the rate of fatal myocardial events 30,48. The importance of finding an increase in nonfatal events in the first 3 months may be of little importance in terms of recent studies showing long-term reductions in mortality with effective TRT.
A study involving 6355 men treated with intramuscular testosterone and followed up for 5 years, showed no increased risk overall but for men with high risk of MI, but testosterone was moderately protective against MI in higher risk patients 39. Considerable clarification is provided by Anderson et al.49, who studied major adverse coronary events and mortality at 1 and 3 years in 5695 men (mean age 62) according to the levels of serum testosterone achieved on therapy and demonstrated a significant reduction in overall mortality but not incidence of MI or stroke (Fig. 1a). This study confirms that the major benefit of TRT is to reduce mortality and not necessarily the absolute number of events, explaining why studies focusing exclusively on short term nonfatal events rather than long-term mortality in inadequately treated patients produced inappropriate and confusing media messages.
A meta-analysis of 1000 patient years 50 versus placebo suggests a slight reduction in MI and cerebral vascular accident but a reduction in coronary interventions. There was a 6% incidence of raised haematocrit (>50%) without significant consequences and no cardiac deaths in the active treatment group versus five in the placebo cohort. Another systematic and meta-analysis of placebo-controlled trials of T therapy lasting more than 12 weeks concluded that testosterone therapy may increase the risk of cardiovascular-related events 51 but most studies involved small cohorts with a small number of events but once again the nonrandomized studies failed to consider the impact of symptoms as an indication for TRT prescribing. A meta-analysis by Corona et al.52 conducted a further meta-analysis and was critical of the selection of papers by Xu et al.51 and the profound influence of the TOM Study 35 on the outcome, concluding that there was no evidence of increased cardiovascular risk with TRT.
Older men with low testosterone usually present with bothersome symptoms, particularly ED, and require treatment to address those problems and improve their quality of life. These men require proper diagnosis and cardiovascular assessment prior to commencing therapy. The benefits of conventional cardiovascular risk reduction with exercise and weight reduction are fundamental to management but are frequently unsuccessful. There is a considerable body of evidence that low testosterone is associated with increased cardiovascular and cancer mortality and that effective TRT reduces mortality rather than the absolute number of coronary events or stroke. A policy of taking little or no action for these men based on concerns of increased cardiovascular risk associated with physiological replacement would seem illogical. There is considerable evidence of modest cardiac and metabolic benefits that are shown to especially reduce cardiovascular mortality. There are sexual, mood, and quality of life changes associated with restoring testosterone levels. These may add up to substantial benefit to many patients and these benefits may potentially be denied to patients by fears over prostate and cardiac risk that is not currently supported by evidence. Ideally, we need large long-term studies to resolve these issues with certainty but such studies are unlikely to be done for logistic, ethical and financial reasons. Until then, patients require advice and treatment based on current best evidence.
Conflicts of interest
Dr G. I. Hackett has received research grants and acts as an occasional speaker for Bayer plc, Lilly plc and Menarini plc.
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