HOW TO TREAT 31 according to defined treatment goals agreed between the patient and practitioner .
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HOW TO TREAT 31 according to defined treatment goals agreed between the patient and practitioner .
Exclude contraindications ( see table 1 ) if testosterone treatment is considered in older men . Because symptoms of androgen deficiency should improve within 1-3 months , a therapy trial of 3-6 months is usually sufficient . Although the somatic effects of testosterone treatment , such as bone mineral density gains , require longer treatment , testosterone should generally not be used for these indications in asymptomatic men given that more effective therapeutic alternatives are available ( see table 3 ).
The initial use of short-acting testosterone formulations minimises the risk of iatrogenic hypogonadism if testosterone treatment is stopped because of lack of benefit . In men suitable for long-term testosterone therapy , long-acting IM testosterone is available ( see table 2 ). Choice depends on patient and physician preference .
The therapeutic target is serum testosterone levels in the low to mid-normal range for healthy young men . Avoid on treatment testosterone levels that are higher than mid-normal , as there is evidence that it might be harmful in older men . A 2014 Australian observational study of older men reported that men with mid-normal testosterone levels between 9.8 and 15.8nmol / L had the lowest mortality , while older men either below or above this range were more likely to die . 14 Similarly , a 2013 RCT found a correlation between the increased risk of cardiovascular events during testosterone therapy and higher on-treatment serum testosterone levels . 15 In men with organic hypogonadism , testosterone replacement rectifies the clinical features of hypogonadism ( except fertility ), although the evidence , for ethical reasons , is limited to uncontrolled studies . 16
The following sections predominantly focus on double blind placebo controlled RCTs of testosterone treatment in men with age-related reductions of serum testosterone ; men with organic hypogonadism were generally excluded from these RCTs .
SEXUAL FUNCTION , ENERGY / VITALITY , COGNITION AND MOOD In the Testosterone Trials ( TTrials ), the most definitive trial to date , recruiting men ( n = 790 ) with clinical evidence of hypogonadism and a serum testosterone of less than 9.54nmol / L , testosterone treatment improved 10 of 12 measures in sexual activity , with standardised mean differences ( SDM ) up to 0.45 ( SMDs of 0.2-0.5 represent a modest treatment effect ). Treatment-associated increases in serum testosterone ( and oestradiol ) were associated with increased sexual desire and activity . 17
The effect of testosterone on erectile function is modest ( an increase of 2.64 points in the erectile function domain of the international index of erectile function score [ IIEF ], see figure 8 ), in the TTrials . This increase is below the minimally important clinical difference ( which is around 4 points ) and less than reported in most RCTs of PDE5-I treatment ; these drugs improve IIEF-EFD by 5-7 points . 18
Consistent with findings in the TTrials , a meta-analysis of RCTs reported that while testosterone treatment improved libido , and overall sexual satisfaction , the effects on erectile function were modest , with an IIEF-EFD score of 2.3 ( again below the clinically significant threshold of ~ 4.0 ). In this meta-analysis , effects on erectile function were blunted in men with diabetes and obesity . 19
Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men ( TRAVERSE ) is the largest and longest testosterone trial to date . It was designed to “ determine the effects of testosterone-replacement therapy on the incidence of major adverse cardiac events among middle-aged and older men with hypogonadism and either preexisting or a high risk of cardiovascular disease ”. 20 Testosterone did not improve erectile function in men at high risk of or with cardiovascular disease . These findings are consistent with the notion that erectile dysfunction in older men commonly has a neuro-vascular origin , especially if there is comorbid cardiovascular disease or diabetes . Moreover , testosterone treatment does not improve erectile function in men with a low testosterone following optimisation of PDE5-I treatment . 21 Overall , the data suggest that while testosterone may improve libido , it generally does not improve erectile dysfunction .
In the TTrials , while testosterone treatment in the primary endpoint analysis had no benefit on vitality assessed as a predefined threshold increase , testosterone treatment was associated with small improvements in vitality , mood and depressive symptoms in exploratory analyses . There was no effect on cognition . 18 Overall , therefore , in men meeting the inclusion criteria of the TTrials , testosterone treatment can be expected to improve most aspects of sexual function , and may lead to small improvements in vitality , mood and depressive symptoms . Erectile dysfunction responds better to a PDE5-I , and the added value of testosterone treatment in men receiving optimised PDE5-I treatment requires further study .
ERYTHROPOIESIS Given the erythropoietic actions of testosterone , it is not surprising that among a subset of men participating in the TTrials who had baseline anaemia ( n = 126 , baseline haemoglobin 100-127g / L ), 50 % of testosterone-treated men reached the primary endpoint , an increase in haemoglobin concentration of 10g / L ( an increment reported in previous anaemia trials to have a positive effect on quality of life ), compared with 15 % randomised to placebo ( adjusted odds ratio ( OR ) 31.5 , 95 % CI 3.7 – 277.8 ; p = 0.002 ). 22 Thus , in men with otherwise unexplained anaemia , testosterone treatment can increase haemoglobin , although the extent to which this translates into patient important health benefits ( for example , reduction in fatigue if present or an increase in exercise capacity ) has not yet been studied . Note that erythrocytosis ( a haematocrit greater than 4 %) is one of the most common adverse effects of testosterone treatment , with a relative risk of 8.14 [ 95 % CI : 1.87 ; 35.40 ] in a recent meta-analysis . 23
MUSCLE STRENGTH AND PHYSICAL FUNCTION Increased lean mass ( by about 1.6- 4.7kg ) is one of the most consistent
24 , 25 effects of testosterone treatment , and in older men with mobility
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Figure 2 . Calf vein thrombosis with a non-compressible , thrombus-filled calf vein .
Figure 3 . Polycythaemia .
Figure 4 . Coronary angiography of a critical sub-occlusion of the common trunk of the left coronary artery and the circumflex artery .
limitations , testosterone improves aspects of muscle strength such as leg-press strength and stair-climbing power . 26
In the TTrials , testosterone treatment improved walking distance ( assessed by the six-minute walking test ) and improved self-reported walking ability , but it did not reduce falls risk . 27
GLUCOSE METABOLISM Testosterone reduces fat mass by about 1.6-4.3kg , 24 , 25 but it does not consistently improve measures of insulin resistance or glycaemic control in men with established diabetes . 28 However , the 2012 testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle program ( T4DM ), a two-year RCT in
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1007 men at high risk of diabetes , reported that testosterone treatment reduced the risk of prevalent diabetes by 44 %, as assessed by an oral glucose tolerance test , above and beyond the effects of a lifestyle program alone . Of note , testosterone treatment had no effects on HbA1c . Given the erythropoietic actions of testosterone , HbA1c may not be the ideal metric