An update on the role of testosterone replacement therapy in the management of hypogonadism

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1 617648TAU / Therapeutic Advances in UrologyG Hackett research-article2015 Therapeutic Advances in Urology Review An update on the role of testosterone replacement therapy in the management of hypogonadism Geoffrey Hackett Ther Adv Urol 2016, Vol. 8(2) DOI: / The Author(s), Reprints and permissions: journalspermissions.nav Abstract: While US testosterone prescriptions have tripled in the last decade with lower trends in Europe, debate continues over the risks, benefits and appropriate use of testosterone replacement therapy (TRT). Some authors blame advertising and the availability of more convenient formulations whilst other have pointed out that the routine testing of men with erectile dysfunction (a significant marker of cardiovascular risk) and those with diabetes would inevitably increase the diagnosis of hypogonadism and lead to an increase in totally appropriate prescribing. They commented that this was merely an appropriate correction of previous underdiagnosis and undertreatment by adherence to evidence-based guidelines. Urologists and primary care physicians are the most frequent initiators of TRT, usually for erectile dysfunction. Benefits are clearly established for sexual function, increase in lean muscle mass and strength, mood and cognitive function, with possible reduction in frailty and osteoporosis. There remains no evidence that TRT is associated with increased risk of prostate cancer or symptomatic benign prostatic hyperplasia, yet the decision to initiate and continue therapy is often decided by urologists. The cardiovascular issues associated with TRT have been clarified by recent studies showing clearly that therapy associated with clear rise in testosterone levels are associated with reduced mortality. Studies reporting to show increased risk have been subject to flawed designs with inadequate baseline diagnosis and follow-up testing. Effectively they have compared nontreated patients with undertreated or on-compliant subjects involving a range of different therapy regimens. Recent evidence suggests long acting injections may be associated with decreased cardiovascular risk but the transdermal route may be associated with potentially relatively greater risk because of conversion to dihydrotestosterone by the effect of 5α reductase in skin. The multiple effects of TRT may add up to a considerable benefit to the patient that might be underestimated by the physician primarily concerned with his own specialty. This paper will attempt to identify who should be treated, and how they should be treated safely to achieve best outcomes, based on a comprehensive MEDLINE and EMBASE and Cochrane searches on hypogonadism, TRT and cardiovascular safety from May 2005 to May This revealed 1714 papers with 52 clinical trials and 32 placebo-controlled randomized, controlled trials. Keywords: hypogonadism, type 2 diabetes, testosterone replacement therapy, cardiovascular safety Prevalence of hypogonadism and associations with comorbidities The prevalence of hypogonadism in men 45 years or older is 12 38% [Mulligan et al. 2006; Dhindsa et al. 2010] and it increases with age, BMI and in the presence of type 2 diabetes, where the prevalence is 35 40% [Dhindsa et al. 2010]. Kaufman and Vermeulen have reviewed the literature and reported that approximately 20% of men over the age of 60 have a serum total T concentration of 320 ng/dl with variation between different populations. Borst and Yarrow reported that 24% of men over 60 have a serum total T of 300 ng/dl (10.4 nmol/l). Correspondence to: Geoffrey Hackett, MD Consultant in Urology and Sexual Medicine, Heartlands Hospital, Birmingham, UK Holly Cottage Clinic, Fisherwick Rd., Lichfield, WS14 9JL Staffordshire, UK geoff.hackett@virgin.net 147

2 Therapeutic Advances in Urology 8(2) The available data suggest that low testosterone in older men is the accumulation of comorbidities associated with age [Wu et al. 2010]. Healthy aged men have minimal or no decline in testosterone concentrations [Wu et al. 2010]. Data from the European Male Ageing Study (EMAS) involving a population of 2599 men (mean BMI 27) aged followed up for 5 years found a prevalence of secondary HG of 11.6%, primary HG of 2% and compensated HG of 9.5% [Tajar et al. 2010]. The three sexual symptoms of erectile dysfunction (ED), loss of morning erections and low libido best predict low testosterone levels [Wu et al. 2010]. ED and low testosterone independently predicted increased mortality both in the general population and in high-risk groups such as those with heart disease and diabetes [Tajar et al. 2010]. Longitudinal observational studies show that low testosterone concentrations are associated with an increase in the incidence of cardiovascular and all-cause mortality [Pye et al. 2014; Khaw et al. 2007; Shores et al. 2006; Oh et al. 2002; Yeap et al. 2014], and that low testosterone and low sex hormone binding globulin (SHBG) predict later onset of type 2 diabetes mellitus (T2DM) and metabolic syndrome, independent of obesity and comorbidities [Stellato et al. 2000; Haffner et al. 1996]. These studies suggest that the relationship between low testosterone and chronic illness, metabolic syndrome and T2DM is bidirectional [Wu et al. 2010; Tajar et al. 2010; Pye et al. 2014]. ED and low testosterone have been clearly shown to significantly impact quality of life in men with T2DM [Brooke et al. 2014]. Given the strength of evidence that low testosterone is associated with increased allcause mortality, it is intuitive that appropriate testosterone replacement therapy (TRT) would reduce mortality. Whilst several studies, especially in T2DM, suggest that this is the case [Shores et al. 2012; Muraleedaran et al. 2013; Sharma et al. 2015; Baillargeon et al. 2014; Hackett et al. 2015], some retrospective studies, often with no baseline assessment or evidence of adequate follow up, suggest that there might be risk associated with TRT [Vigen et al. 2013; Finkle et al. 2014]. These confusing messages may prevent men with clear indication for treatment from receiving entirely appropriate TRT. Many physicians take the approach that low testosterone is predominantly a consequence of chronic ill health and obesity, quoting small studies in which long-term intensive life intervention improves testosterone levels [Corona et al. 2013b], although long-term follow up from the EMAS study suggests weight loss is associated with minimal symptomatic benefit [Rastelli et al. 2015], especially in men with comorbidities [Wing et al. 2010]. There is clear evidence from multiple studies that around 20% of patients achieving 10% weight loss maintain it for longer than 1 year despite intense dietary intervention [Wing and Phelan, 2005]. Despite this evidence, some authors suggest that lifestyle change should be tried first in all patients [Rastelli et al. 2015]. In the case of T2DM, well developed primary care systems have trialed multiple interventions, including unlimited free dietician advice, lifestyle coaching, free exercise classes and gym memberships [Home et al. 2008], yet the diabesity epidemic increases [Wing and Phelan, 2005] and mortality rates remain unacceptably high, with the impact of HG being consistently high in men with T2DM [Corona et al. 2013b]. The common sense approach is to discuss the impact of treatment based on the severity of symptoms and allow the patient to decide which option suits his needs. Some might be happy to wait 2 years or more to assess the impact of lifestyle modification, but for most who have sought medical attention, the impact and severity of symptoms demands combined therapy with TRT, ED therapy and lifestyle modification as suggested by UK guidelines [Wylie et al. 2010]. How do guidelines help us? The International Society for Study of the Ageing Male, the European Urology Association and the British Society for Sexual Medicine Association [Wylie et al. 2010; Wang et al. 2009; Dohle et al. 2015] suggest that a level of TT of less than 8 nmol/l or free testosterone of less than 180 pmol/l in the presence of physical symptoms requires TRT and TT of more than 12 nmol/l or free testosterone of more than 225 pmol/l. Between these levels a trial of therapy for a minimum of 6 months should be considered based on symptoms [Wylie et al. 2010; Dohle et al. 2015] TT should be measured between the hours of 7 and 11 am on two occasions at least 1 month apart and ideally be assessed by gas chromatography/ mass spectrometry. Equilibrium dialysis is currently the gold standard for free testosterone as immunoassays based on analogue displacement are currently inaccurate [Wylie et al. 2010; Wang et al. 2009; Dohle et al. 2015, Bhasin et al. 2010]. The National Institute for Health and Care 148

3 G Hackett Excellence recommends that all men with T2DM should be asked annually about ED, assessed and treated according to current guidelines [Home et al. 2008], which in Europe, recommend testosterone measurement as mandatory in all cases [Wylie et al. 2010; Dohle et al. 2015]. Following these guidelines will certainly increase the diagnosis of hypogonadism (HG) and uncover increasing numbers of men who are candidates for treatment, irrespective of media advertising. The Endocrine Society (ES) [Bhasin et al. 2010] recommends that men with the following conditions should be considered at high risk of HG: 1. Type 2 diabetes 2. Metabolic syndrome 3. Moderate to severe chronic lung disease 4. Osteoporosis, 5. Human immunodeficiency virus 6. History of infertility 7. Treatment with steroids, opiates (even medically prescribed), and anticonvulsants 8. Alcohol abuse 9. ED or loss of spontaneous erections 10. Loss of sexual desire The ES [Bhasin et al. 2010] recommends testosterone therapy for men with symptomatic androgen deficiency to induce and maintain secondary sex characteristics and to improve their sexual function, sense of wellbeing, muscle mass and strength, and bone mineral density (BMD). They recommend TRT for men with frank compensated HG defined as less than 250 ng/dl (8.7 nmol/l) [Bhasin et al. 2010]. Normal laboratory values vary considerably, adding to the difficulty of standardized definition. Even more confusion exists around what constitutes the symptomatic patient. The urologist often deals with patients referred for sexual dysfunction and is well aware of the impact on the patient, whereas endocrinologists frequently fail to routinely assess and manage sexual dysfunctions [Dohle et al. 2015]. The ES stops short of recommending screening in high-risk groups such as T2DM [Bhasin et al. 2010] but with ED rates of 78% and depression of 25% [Hackett et al. 2014], most patients are highly symptomatic and merit screening according to guidelines on sexual dysfunction. Data from the Birmingham, Lichfield, Atherstone, Sutton and Tamworth (BLAST) study suggest that less than 5% of men with T2DM would be asymptomatic by questionnaire and have normal erectile function, meaning effectively that 95% of men with T2DM require testosterone measurement based on ES recommendations, assuming a thorough history has been taken. The ES recommends against starting testosterone therapy in patients with breast or prostate cancer, a palpable prostate nodule or induration or prostate-specific antigen greater than 4 ng/ml or greater than 3 ng/ml in men at high risk of prostate cancer, such as African Americans or men with first-degree relatives with prostate cancer without further urological evaluation, hematocrit greater than 50%, untreated severe obstructive sleep apnea (OSA), severe lower urinary tract symptoms with International Prostate Symptom Score above 19, or uncontrolled or poorly controlled heart failure [Bhasin et al. 2010]. Recent long-term studies, however, suggest no increased risk of prostate cancer [Dohle et al. 2015], possible improvement in lower urinary tract symptoms, no adverse effect on OSA after the first few weeks [Dohle et al. 2015], low testosterone is associated with increased mortality and hospital admission from heart failure, and that TRT improves heart failure [Santos et al. 2015]. Current medical opinion in the USA is that TRT should be prescribed for older men with either low serum testosterone or low testosterone plus accompanying symptoms of HG [Wylie et al. 2010; Wang et al. 2009; Bhasin et al. 2010]. The paradox is that testosterone levels are not routinely measured in the conditions recommended by the ES, meaning that physicians do not put themselves in a position to detect frank HG and make appropriate clinical decisions. Treatment for men who simply have low testosterone remains somewhat controversial, but the likelihood is that most of these men may have symptoms of importance to them and continue to take TRT because of symptomatic benefit. TRT and cardiometabolic risk profile Low testosterone is associated with a fourfold risk of developing T2DM in men and an Australian study (T4DM) to be published in 2016/7 (www. t4dm.org.au) should address the important issue as to whether TRT will reduce the risk of newonset T2DM [Stellato et al. 2000; Haffner et al. 1996]. It used to be believed that testosterone treatment adversely affects cardiovascular risk 149

4 Therapeutic Advances in Urology 8(2) Table 1. Outcome of therapy with long-acting TU in men with type 2 diabetes and hypogonadism (Birmingham, Lichfield, Atherstone, Sutton and Tamworth, BLAST) [Hackett et al. 2014]. HbA1c (%) >7.5 Weight (kg) BMI (kg/m 2 ) WC (cm) TC (mmol/l) EF (IIEF) AMS (patients) HADSD GEQ (% imp) 30 weeks p value < weeks PDE5I p value < AMS, Aging Male Symptom; BMI, body mass index; HbA1c, hemoglobin A1c; PDE5I. phosphodiesterase type 5 inhibitor; TC, total cholesterol; WC, waist circumference; EF, erectile function domain of International Index of Erectile Function; HADS, Hospital Anxiety and Depression Score; IIEF, International Index of Erectile Function; GEQ, Global Efficacy Question. because it lowers high-density lipoprotein (HDL) cholesterol concentration. However, that effect is predominantly restricted to treatment that achieves supranormal concentrations of testosterone, for example, during abuse of androgens for body building [Borst and Yarrow, 2015]. TRT has not been shown to cause any meaningful change in HDL concentrations in studies in which testosterone is replaced to normal levels, while many cardiovascular risk factors are changed favorably [Traish et al. 2014; Saad et al. 2015; Haider et al. 2014]. TIMES2 (Testosterone Replacement in Hypogonadal Men with type 2 diabetes or Metabolic Syndrome) studied the effects of TRT in 220 men with HG and T2DM or metabolic syndrome in a multicenter, randomized, double-blind, placebo-controlled study [Khaw et al. 2007]. TRT improved insulin resistance, total and low-density lipoprotein (LDL) cholesterol, lipoprotein (a), body fat composition and sexual function over a 6-month period [Jones et al. 2011]. The BLAST study showed improvements of 0.4% in glycated hemoglobin (HbA1c) at 6 months versus placebo and 0.87% after a further 12 months. The authors also showed reductions in total cholesterol (TC), LDL plus BMI, weight and waist circumference, along with improvements in sexual function and quality of life (Table 1) [Hackett et al. 2014]. A 5-year registry of 255 men aged [Traish et al. 2014] treated with long-acting testosterone undecanoate (TU) 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% ( ) [Traish et al. 2014]. Nine-year data suggest that the metabolic and symptomatic benefits may be at least as great in older men [Saad et al. 2015]. A feature of published registries is the low rates of cardiac and prostate-related events [Traish et al. 2014; Saad et al. 2015]. TRT in these individuals resulted in significant and sustained improvements in weight, waist circumference, HbA1c, TC:HDL ratio and C-reactive protein (CRP) [Saad et al. 2015; Haider et al. 2014]. Kalinchenko and colleagues studied 184 men with HG and metabolic syndrome to receive placebo or parenteral TRT. After 30 weeks of randomization, TRT recipients had significant decreases in weight, waist circumference, insulin levels and CRP [Kalinchenko et al. 2010]. Francomano and colleagues in a prospective case control study demonstrated that TRT in patients with HG resulted in improvement in obesity, blood pressure, and glycemic control and BMD [Francomano et al. 2014]. Aversa and colleagues demonstrated significant decrease in carotid intima media thickness after 12 months of parenteral TRT in a randomized, placebo-controlled trial in men with HG and metabolic syndrome [Aversa et al. 2010]. These results suggest a large number of modest improvements may add up to significant risk reduction when assessed together, rather than in isolation. Other benefits of TRT TRT produces a number of established benefits in men with HG, including increased muscle mass and strength, decreased fat mass, increased BMD, improved sexual function and cognitive function. Improvements in sexual function are not only in terms of erectile function but are seen in desire, ejaculation, orgasm and intercourse, and relationship satisfaction [Hackett et al. 2013]. TRT also upregulates phosphodiesterase type 5 inhibitors (PDE5Is), converting previous responders to responders [Buvat et al. 2011], and this effect 150

5 G Hackett alone is a possible justification for TRT as secondand third-line ED therapies usually have low acceptability rates for patients and couples. Men over the age of 65 are subject to an increased incidence of osteoporosis and to increased falls and fractures ultimately contributing to increased mortality [Ferrando et al. 2002; Meier et al. 2008]. In older men, low serum testosterone is associated with osteopenia [Meier et al. 2008; Tracz et al. 2006] and increased fracture risk, particularly the lumbar vertebrae [Tracz et al. 2006]. Testosterone administration increases BMD, mainly by suppressing bone resorption [Ferrando et al. 2002]. TRT may increase BMD in men by a direct androgen receptor (AR)-mediated effect of testosterone or by an indirect action requiring conversion to estradiol [Bliuc et al. 2015; Tracz et al. 2006]. A 2006 meta-analysis of eight TRT trials in older men with HG found that intramuscular TRT produced a significant 8% increase in lumbar spine BMD and a nonsignificant 4% in hip BMD, while transdermal TRT produced no increases in BMD [Tracz et al. 2006] In this regard, low serum estradiol is more strongly associated with osteopenia in older men than is low serum T [Tracz et al. 2006; Laurent et al. 2013]. Interestingly, the indirect effects of testosterone may be more important than the direct effects, as evidenced by the work of Falahati-Nini and colleagues [Falahati-Nini et al. 2000]. The important concept of frailty These aspects are often misjudged by physicians who underestimate the importance of all these factors in the ageing man [European Union, 2011]. In some cases such benefits are dose dependent [Tracz et al. 2006]. For example, doses of TRT administered by long-acting intramuscular injection are typically higher than those administered transdermally, which results in greater musculoskeletal benefits [Ferrando et al. 2002; Borst and Yarrow, 2015]. The overall impact of these multiple effects is a potential for reduction in frailty and recurrent falls are strongly related to impaired cognitive function and reduced muscle strength [Ferrando et al. 2002; Srinivas-Shankar et al. 2010]. The added effect of osteoporosis combined with increased risk of recurrent falls increases fracture risk, leading to increased mortality and hospitalization [European Union, 2011]. Whilst men consume fewer health resources than women under 65, this rapidly changes over 75 due to the impact of frailty [European Union, 2011]. Long-term studies to establish these benefits have proved difficult logistically, especially after the early discontinuation of the TOM (Testosterone in Older Men) trial [Laurent et al. 2013] but the Testosterone Trial is due to report in the next 12 months and may answer some questions. The concept of frailty is important in understanding the impact of TRT on all-cause mortality as frailty impacts on chances of surviving most major illnesses associated with ageing. Unfortunately the majority of trials in older people have used transdermal gels which probably have a lower impact than injections on the factors contributing to frailty [Srinivas-Shankar et al. 2010; Borst and Yarrow, 2015]. Positive studies on TRT and cardiovascular safety Prospective studies. A prospective study of 587 men with T2DM [Muraleedaran et al. 2013] involved 5.8 years of follow up. Low testosterone was defined as TT less than 10.4 nmol/l. A total of 58 men were treated with testosterone for 2 years or more. The mortality rate was 20% in the untreated group and 9.1% in the normal group independent of comorbidities and therapies. Mortality was 8.6% in the treated group ( Figure 1). A similar retrospective US study involved 1031 men with 372 on TRT. The cumulative mortality was 21% in the untreated group versus 10% in the treated group [Shores et al. 2012] with the greatest effect in younger men and in those with type 2 diabetes. Both papers were criticized for possible selection bias, but strengths were reliable pretreatment diagnosis and accurate reporting of medications. Baillargeon and colleagues retrospectively compared acute myocardial infarction (MI) rates for 6355 men over 8 years receiving at least one testosterone injection compared with a matched placebo group and found no overall increase in events, including MI, stroke and thromboembolism [Baillargeon et al. 2014]. In the quartile at greatest risk, there was a significant reduction in events and mortality. In a prospective study of 145 patients with T2DM and first ischemic stroke, 66% were found to have HG. In the testosterone-treated group, 7% had a recurrence of stroke in 2 years versus 16.6% in the control group, with 28% of the treated men returning to work versus 6% of the control group. There were significant improvements in lipid profile and HbA1c [Morganuv et al. 2011]

6 Therapeutic Advances in Urology 8(2) Figure 1. Low testosterone (T) predicts increased mortality and testosterone therapy improves survival in 587 men with type 2 diabetes (mean follow up: 5.8 years) [Muraleedaran et al. 2013]. Retrospective studies. Anderson and colleagues retrospectively searched electronic medical records between 1996 and 2011 to identify 5695 men who had a low initial TT level, a subsequent testosterone level, and up to 3 years of follow up [Anderson et al. 2014a]. Levels were correlated with testosterone supplement use. Primary outcomes were a composite of death, nonfatal MI, and stroke [major adverse coronary events (MACE)] and death alone. The authors concluded that TRT therapy in men with low testosterone was associated with reduced MACE and death over 3 years compared with no or ineffective supplementation. This study suggested that the impact of TRT was predominantly on mortality rather than number of events and benefits were associated with achieving therapeutic levels of testosterone (Figure 2). Sharma and colleagues retrospectively examined 83,010 male veterans with documented low TT levels [Sharma et al. 2015]. The subjects were categorized into group 1 (TRT with resulting normalization of TT levels), group 2 (TRT without normalization of TT levels), and group 3 (did not receive TRT). The all-cause mortality [hazard ratio (HR): 0.44, confidence interval (CI) ], risk of MI (HR: 0.76, CI ) and stroke (HR: 0.64, CI ) were significantly lower in group 1 (n = 43,931, median age 66 years, mean follow up = 6.2 years) compared with group 3 (n = 13,378, median age = 66 years, mean follow up = 4.7 years) in a propensity-matched cohort. Similarly, the all-cause mortality (HR: 0.53, CI ), risk of MI (HR: 0.82, CI ) and stroke (HR: 0.70, CI ) were significantly lower in group 1 versus group 2 (n = 25,701, median age 66 years, mean follow up = 4.6 years). This study presents the most compelling evidence to date for the cardioprotective effects of TRT in patients with clearly defined TDS treated to the therapeutic range, suggesting that studies with negative outcomes usually included inadequate diagnosis and little evidence of effective therapeutic levels or adequate follow up (Figure 3). Hackett and colleagues prospectively studied 857 men with T2DM screened and randomized for the BLAST over 4 years and concluded that TRT and the use of PDE5Is were independently associated with reduced mortality with greatest benefit from both drugs being seen in older men (Figure 4) [Hackett et al. 2015]. None of the previous studies had even considered PDE5I use as a confounder. Anderson and colleagues retrospectively studied 7860 men with T2DM and described a 28% reduction in all-cause mortality 152

7 G Hackett Figure 2. Cardiovascular impact of testosterone therapy in 5695 men with low testosterone levels: event rates (%) of major adverse cardiovascular events (MACE) [Anderson et al. 2014a]. f/u, follow up; T, testosterone. Figure 3. Kaplan Meier curve depicting the all-cause mortality among different propensity-matched study groups [Sharma et al. 2015]. Non-norm., non-normalized

8 Therapeutic Advances in Urology 8(2) Figure 4. BLAST (Birmingham, Lichfield, Atherstone, Sutton and Tamworth) diabetes long-term mortality [Hackett et al. 2015; Basaria et al. 2010]. f/up, follow up; PDE5, phosphodiesterase type 5. with PDE5I therapy and a similar improvement in survival following incident acute MI [Anderson et al. 2014b]. Negative studies on TRT and cardiovascular safety Randomized controlled studies. Theoretical concerns around testosterone are associated with rise in hematocrit, a decrease in HDL cholesterol and a possible risk in fibrinogen. Two groups have reported an association of TRT with adverse cardiovascular outcomes. A trial of 209 older frail men [Basaria et al. 2010] over 65 randomized to receive either placebo or 100 g of topical testosterone gel was terminated early as there were 23 cardiac events (two deaths) in the 106 men in the testosterone group versus five in the placebo group, despite positive results in study endpoints. These events included MI and dysrhythmias and hypertension. The authors conceded that there were more cardiovascular comorbidities in the active treatment group and that the starting dose and escalation were outside the product license. The active treatment group had more severe cardiovascular disease. The study involved escalation up to 150 mg per day, above the manufacturer s recommended dose and many of the events were reported with inadequate validation. Retrospective studies. Vigen and colleagues retrospectively reported a composite outcome of allcause mortality, MI and stroke rates in a cohort of men with low testosterone levels who had undergone coronary angiography and subsequently received TRT [Vigen et al. 2013]. The actual reported rate of events was 10.1% for the testosterone-treated group and 21.2% in controls, showing a reduced event rate in the treated group by more than half. However, after statistical adjustment for over 50 variables, the outcome was reversed! The use of TRT was associated with increased risk of adverse outcomes (19.9% in no treatment group versus 25.7% in treated group) 3 years after the angiography. The study has been criticized for its statistical techniques, lack of adjustment for baseline testosterone concentrations, inadequacy of testosterone treatment in study subjects, and some corrections in actual data have been published by the authors. They also inappropriately excluded 128 men who had events in the untreated group but subsequently took testosterone. These would have made a huge difference if included. Sixty-three percent had testosterone patches, which were withdrawn because of high rates of skin irritation which 154

9 G Hackett would have been expected to contribute to high discontinuation rates [Schoenfeld et al. 2013]. The authors also conceded that they wrongly included 104 women. However, the likely explanation for the stark difference between adjusted and actual event rates is probably that the actual effect size of TRT on study points is much smaller than the effect of comorbidities that needed adjustment amongst mismatched groups. In another study, Finkle and colleagues retrospectively examined 55,593 insurance claims and compared the incidence of rate of MI in the 1-year prior and 90 days after initial prescription of TRT [Finkle et al. 2014]. They reported an increased rate of nonfatal MIs, especially with men aged 65 or older. In men younger than 65 the risk was confined to those with preexisting heart disease. There was no control group and there was no information available on testosterone concentrations (pre or post treatment) or of cardiovascular risk factors in subjects who were treated. Furthermore, the treatment duration of 3 months is wholly inadequate for a trial looking at nonfatal cardiac events, especially in the light of studies showing long-term reduction in all-cause mortality. Meta-analyses. A meta-analysis of placebo-controlled trials of testosterone therapy lasting more than 12 weeks by Xu and colleagues concluded that testosterone therapy may increase the risk of cardiovascular-related events but most studies involved small cohorts with a small number of events [Xu et al. 2013]. The authors concluded that Pharma sponsored studies tended to find benefit from TRT whereas independent studies did not [Xu et al. 2013]. The authors were criticized for their selection and inclusion of studies. Findings from the TOM study [Basaria et al. 2010] heavily skewed their findings and the inclusion of a study involving an unlicensed oral formulation in men with advanced liver cirrhosis suggested selection bias. The authors failed to consider that Pharma supported studies frequently involve no influence in design or analysis and may provide adequate resources for proper conduct of the study. A recent meta-analysis by Corona and colleagues was critical of the selection criteria and inappropriate use of statistics for lower powered studies in the Xu paper and concluded that there was no increased risk associated with TRT [Corona et al. 2013a]. The conclusion was that there was no evidence of long-term risk and a suggestion of benefit in men with metabolic syndrome or T2DM. Both papers called for a well powered long-term study but this is unlikely based on cost, especially if industry funding is considered a likely confounder. Rather surprisingly, in March 2015, the US Food and Drug Administration called for future studies of TRT to include assessment of cardiovascular disease and stroke risk [US Food and Drug Administration, 2014]. Is the formulation of TRT important? Many early studies reported results from oral TRT, patches, short-acting injections and implants. The current market is largely long-acting injections and topical gel or solution. Layton and colleagues retrospectively analyzed 544,115 TRT initiations based on computerized data from the US and UK healthcare systems and concluded that short-acting injections had higher event rates, followed by patches and then gels [Layton et al. 2015]. Once again there were no baseline levels to confirm diagnosis and no evidence of treatment compliance, only initiation. It is therefore possible that treatment choice may have reflected many clinical issues, including the severity of deficiency. Certainly therapy discontinuation is highest with short-acting injections followed by patches and then gels [Corona et al. 2013a], suggesting that the increased mortality was more likely related to the severity and undertreatment of testosterone treatment than the therapy itself. A recent meta-analysis by Borst and Yarrow came to the opposite conclusion [Borst and Yarrow, 2015]. Placebo-controlled studies involving injection therapy were associated with a significant reduction in mortality compared with patch and gel studies. They postulated that this was associated with more sustained serum levels and reduced conversion to dihydrotestosterone (DHT) by 5α reductase in skin. Borst and Yarrow reported that transdermal testosterone (patch and gel) elevates serum DHT 5.46 fold, while intramuscular testosterone injection elevates serum DHT only 2.2 fold [Borst and Yarrow, 2015]. Shores and colleagues had earlier described potential adverse cardiovascular risk associated with DHT [US Food and Drug Administration, 2014].This surprising phenomenon occurs despite the fact that transdermal and intramuscular TRT elevated serum testosterone to a roughly similar degree and may be explained by relatively high expression of 5α reductase in skin versus lower expression in skeletal muscle [Shores et al. 2014]

10 Therapeutic Advances in Urology 8(2) Many of the these more positive recent publications in Europe are related to the use of longacting TU, which produces constant sustained levels for up to 12 weeks with improvement in metabolic and sexual parameters and markedly lower withdrawal rates in clinical trials [Hackett et al. 2014; Kalinchenko et al. 2010]. A major advantage is the avoidance of early compliance issues as a single dose ensures adequate dosing to assess response. Follow-up blood tests can be done at any time and are easier to assess in relationship to dosing time, ensuring simplified dosing adjustment [Hackett et al. 2014; Kalinchenko et al. 2010]. There is no risk of partner transfer and less rise in hematocrit due to avoidance of peaks and troughs. Studies suggest a greater improvement in sexual and general wellbeing, related to the achievement of sustained therapeutic levels [Corona et al. 2013a]. Some guidelines suggest 3 6 months as an adequate trial of therapy [Wang et al. 2009; Dohle et al. 2015; Bhasin et al. 2010] but recent evidence suggests 6- and probably 12-month trials are required [Hackett et al. 2014]. Improvement in sexual symptoms are seen first [Hackett et al. 2013, 2014] and these benefits might be underestimated in importance by physicians without an interest in sexual function. Monitoring and follow up Patients require a baseline full blood count, prostate-specific antigen (PSA), TT, SHBG, and prolactin if the TT is below 5.2 nmol/l. An initial luteinising hormone (LH) is required to confirm whether the HG is primary or secondary. Patients need to be asked about future parenthood as TRT will suppress follicle-stimulating hormone) production for 6 9 months. A baseline digital rectal examination is advised for men over 50. Follow up at 3 6 months consists of TT, PSA and full blood count to ensure the hematocrit remains below 54%. As transient rises in PSA are seen within the first 6 months, it is recommended that the PSA 6 months after commencing TRT should be taken as baseline and any future interventions would be in accordance with local policies on PSA. Timing of TT levels is not important for patients on longacting testosterone injections but ideally those on topical gels require measurement 2 4 h after the daily application of gel. The aim is to maintain the patient in the mid to upper normal range. Longterm follow-up visits should be carried out at 12 monthly intervals and can be incorporated into other chronic disease monitoring. The BLAST study suggests that the early sexual benefits and improvements in Aging Male Symptom score in terms of energy levels and muscle strength are the major reason for treatment satisfaction [Hackett et al. 2013, 2014]. The multiple modest effects of TRT equate to highly significant improvements in wellbeing that are greatly appreciated by patients and a major reason why men want to continue with therapy. What does this mean for clinical practice? Patients with HG present with distressing symptoms associated with poor quality of life. They rightly expect their physician to be motivated to treat their symptoms rather than statistical risk and performance targets. TRT is associated with modest improvements in a range of symptoms that might add up to huge benefit to the patient that might be underestimated by a specialist with a defined area of interest. The symptoms of HG cross many specialties and the clinical decision maker needs to be aware of the impact of TDS and the benefits of TRT outside the comfort area of their own specialty. When TRT has been initiated with urologists, usually for sexual dysfunction, therapy may be discontinued because of a rise in PSA, despite strong evidence that TRT does not cause prostate cancer, even though the patient might be achieving symptomatic or even metabolic improvement. The patient will therefore be deprived of the multiple potential benefits of TRT because of transient elevation of a biomarker despite no evidence of any cancer risk. Recent evidence suggests that low testosterone may actually put the patient at increased risk of higher-grade cancers. Clearly decisions on TRT should ideally take into account the total impact on the patient. Trials of treatment need to be for at least 6 and ideally 12 months to achieve levels in the mid to upper normal range, with monitoring according to expert guidelines. The decision to continue with treatment needs to be based on a range of parameters, most importantly the impact that the treatment has had on the overall quality of life of the patient and his partner. There is a strong and consistent body of evidence that TRT for appropriately diagnosed HG is safe, efficacious and probably associated with reduction in cardiovascular risk and all-cause mortality. Crucially studies assessing mortality based on appropriate diagnosis achieving target therapeutic levels consistently show reduced mortality whereas two high-profile studies showing 156

11 G Hackett increased mortality were flawed by lack of definite diagnosis and no evidence of adequate therapy. In many cases single prescriptions counted as treatment and less than 40% had any recorded follow up. Studies using this methodology to assess the impact of thyroxine to treat hypothyroidism would never have been published. Patients generally choose to take and continue TRT because of symptomatic benefit and improved quality of life, not because of risk reduction. Unfortunately a few poorly designed studies from the USA with inadequate diagnosis and follow up apparently showed increased risk with TRT. These received inappropriately high-profile coverage when their methodology was severely flawed. We need more balance and less hysteria in future research and media coverage. The perfect longterm placebo-controlled trial to answer all these issues will probably never be conducted on ethical and cost grounds as HG is a highly symptomatic condition with a defined effective licensed treatment, The Australian T4DM study ( org.au) might answer important questions about diabetes prevention with TRT in younger men with obesity by The Testosterone Trial ( cceb.upenn.edu/portal/page/portal/t-trial%20 Portal/T-TrialPublicPageMain) will hopefully deal with issues around muscle strength and frailty in older men within 2 years. Neither will be powered to deal with cardiovascular safety. In the meantime, we need to offer our patients the best advice for them, based on current best evidence. Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors. Conflict of interest statement The authors declare that there is no conflict of interest. References Anderson, J., May, H., Lappe, D., Bair, T., Le, V. and Muhlestein, J. (2014a) Abstract 13220: Cardiovascular impact of testosterone therapy in men with low testosterone levels. Circulation 130. Available at: A13220.abstract?sid=de950f72-261c-46b7-b6e b90 (accessed 24 November 2014). Anderson, S., Hutchings, D., Kwok, C., Trafford, A. and Heald, A. (2014b) Phosphodiesterase type-5 inhibitor use in type 2 diabetes is associated with a reduction in all cause mortality7-lb. Artery Res 8: 148. Aversa, A., Bruzziches, R., Francomano, D., Rosano, G., Isidori, A., Lenzi, A. et al. (2010) 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. J Sex Med 7: Baillargeon, J., Urban, R., Kuo, Y., Ottenbacher, K., Raji, M., Du, F. et al. (2014) Risk of myocardial infarction in older men receiving testosterone therapy. Ann Pharmacother 48: Baillargeon, J., Urban, R., Ottenbacher, K., Pierson, K. and Goodwin, J. (2013) Trends in androgen prescribing in the United States, 2001 to JAMA Intern Med 173: Basaria, S., Coviello, A., Travison, T., Storer, T., Farwell, W., Jette, A. et al. (2010) Adverse events associated with testosterone administration. N Engl J Med 363: Bhasin, S., Cunningham, G., Hayes, F., Matsumoto, A., Snyder, P., Swerdloff, R. et al. (2010) Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 95: Bliuc, D., Nguyen, N., Alarkawi, D., Nguyen, T., Eisman, J. and Center, J. (2015) Accelerated bone loss and increased post-fracture mortality in elderly women and men. Osteoporos Int 26: Borst, S., Shuster, J., Zou, B., Ye, F., Jia, H., Wokhlu, A. et al. (2014) Cardiovascular risks and elevation of serum DHT vary by route of testosterone administration: a systematic review and meta-analysis. BMC Med 12: 211. Borst, S. and Yarrow, J. (2015) Injection of testosterone may be safer and more effective than transdermal administration for combating loss of muscle and bone in older men. Am J Physiol Endocrinol Metab 308: E1035 E1042. doi: / ajpendo Brooke, J., Walter, D. and Kapoor, D. (2014) Testosterone deficiency and severity of erectile dysfunction are independently associated with reduced quality of life in men with type 2 diabetes. Andrology 2: Buvat, J., Montorsi, F., Maggi, M., Porst, H., Kaipia, A., Colson, M. et al. (2011) Hypogonadal men nonresponders to the PDE5 inhibitor tadalafil benefit from normalization of testosterone levels with a 1% hydroalcoholic testosterone gel in the treatment of erectile dysfunction (TADTEST study). J Sex Med 8: doi: /j x 157

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