32 HOW TO TREAT : MANAGEMENT OF LOW TESTOSTERONE IN MEN
32 HOW TO TREAT : MANAGEMENT OF LOW TESTOSTERONE IN MEN
9 AUGUST 2024 ausdoc . com . au to assess glycaemic changes during testosterone treatment . 29 In T4DM , the effect of testosterone treatment on diabetes reduction was largely mediated by a reduction in fat mass , emphasising the importance of limiting adiposity for diabetes prevention .
BONE HEALTH A 2005 meta-analysis of RCTs of using conventional dual-energy X-ray absorptiometry ( DXA ) reported that testosterone treatment increased areal BMD at the lumbar spine ( by 3.7 % compared with placebo ), while there was no significant increase in areal BMD at the femur . 24 However , a 206 larger study of 600 men reported that testosterone treatment over two years was associated with increased areal BMD at the femur , both the total femur as well as the femoral neck . 30 In addition , studies using quantitative CT and high-resolution peripheral quantitative CT ( HR-pQCT ) have reported that testosterone treatment improves volumetric bone density , both at cortical and trabecular sites , and improves estimated bone strength . 30 , 31 Men in these studies had normal bone density at baseline , 30 , 31 and the effects of testosterone treatment on bone architecture and strength in men with osteoporosis are less well established .
Of note , a secondary analysis of the TRAVERSE cardiovascular study has reported that , surprisingly , testosterone treatment is associated with an increase in fracture risk ( mostly traumatic fractures such as ribs or ankle ) especially within the first 3-6 months of testosterone initiation . 32 The early effects suggest behavioural mechanisms , perhaps related to increased activity or even risky behaviour . 33 While this does not mean that testosterone should be withheld for men with organic hypogonadism who need testosterone replacement for optimal health , older men should be counselled about this risk . This reinforces the important concept that men at high fracture risk require osteoporotic drug therapy with medications that have a proven anti-fracture benefit , irrespective of whether testosterone treatment is considered or not .
CARDIOVASCULAR HEALTH In some observational studies , increased serum testosterone has been associated with a decreased risk of cardiovascular events . 34 However , these studies may be confounded because low testosterone reflects unmeasured comorbidities that may increase cardiovascular risk . Retrospective nonrandomised trials of testosterone treatment have suggested either reduced risks of cardiovascular events , neutral effects or increased risks . 35-37 These retrospective studies have significant methodologic shortcomings , including studies with confounding by indication ( that is , preferential treatment of healthier men ) and potential for multiple sources of biases .
Clinical trials of testosterone treatment have likewise been mixed , with one study in older men with mobility limitations reporting an increased risk of cardiovascular events , while no increase was reported in a similar trial in frail older men . 38 , 39 Most recent larger clinical trials have excluded men at high risk of cardiovascular events , 18 , 29 and current Endocrine Society guidelines recommend against testosterone therapy in men with uncontrolled heart failure , myocardial infarction or stroke within the last six months , or with thrombophilia . 40
The 2023 TRAVERSE trial is the first RCT designed specifically to assess the cardiovascular effects of testosterone in older men . 20 TRAVERSE is a multicentre , randomised , double-blind , placebo-controlled , noninferiority US trial . The trial enrolled 5246 men aged 45-80 with pre-existing or a high risk of cardiovascular disease , who reported symptoms of hypogonadism and who had two fasting testosterone concentrations of less than 12.4nmol / L . Many men were obese , and it is possible that some enrolled men had ‘ pseudo-hypogonadism ’; that is , mildly reduced serum testosterone from obesity-associated reductions in SHBG , and would thus not have been considered suitable candidates for testosterone treatment in Australia .
The mean duration of treatment was 21.7 months , and the mean follow-up 33 months . A primary cardiovascular end-point event ( defined as the composite of death from cardiovascular causes , non-fatal myocardial infarction , or non-fatal stroke ) occurred in 182 patients ( 7.0 %) in the testosterone group and in 190 patients ( 7.3 %) in the placebo group ( hazard ratio , 0.96 ; 95 % confidence interval , 0.78 to 1.17 ; P < 0.001 for noninferiority ). 20 The incidence of each of the events of the composite primary cardiovascular endpoint appear similar in the two groups .
Overall , the trial suggested the cardiovascular safety of testosterone with respect to the primary endpoint , at least in the short term . However , the trial did report a higher incidence of atrial fibrillation , acute kidney injury and pulmonary embolism in the testosterone group , findings of concern that require further study .
PROSTATE HEALTH Testosterone therapy typically increases serum prostate-specific antigen ( PSA ) because the prostate gland is an androgen-dependent organ . While there is no current evidence that testosterone treatment increases the risk of de novo prostate cancer , clinical trials have not been large enough to determine the true risk . It is not known whether testosterone treatment stimulates the growth of pre-existing subclinical prostate cancer . Testosterone treatment has not been shown to have a significant effect on lower urinary tract symptoms . 23 However , clinical trials have generally excluded men with severe benign prostatic hypertrophy .
Testosterone should not be prescribed for men with existing prostate cancer or those at high risk ( unevaluated prostate nodule , PSA greater than 3-4ng / mL ), and follow-up of prostate health during testosterone treatment should be individualised ( see table 1 ). 40
CASE STUDIES
Case study one
CHARLES , a 65-year-old man , presents with erectile function , fatigue and low mood . He recently had a normal sleep study . He has a three-year history of type 2 diabetes treated with metformin . Charles had an acute myocardial infarction two years ago . At the time , he had a coronary angiography , and a cardiologist recommended medical management . Findings on recent stress echocardiography were reported as normal .
Table 2 . Testosterone formulations currently available in Australia
Preparation / administration
Testosterone gel ( see figure 5 ) 1 %, 2 % #
or 5 % cream^ Daily
Testosterone undecanoate 1g IM injection
Three-monthly
Advantages Disadvantages Testosterone monitoring
Can be selfadministered
Short half-life *
Convenience Compliance
Stable testosterone levels
Chance for inadvertent transfer to close contacts ( spouse , children , nurses )
Imprecise dose adjustment Marked variation in blood levels Skin irritation
Injection site pain
Contraindicated in men with coagulopathies or thrombocytopenia
Cannot be self-administered
Post-injection cough from pulmonary oil micro-embolism
Morning , before application , after use for seven days
Aim for serum testosterone concentrations in the middle of the assay reference range
Morning , before the fourth injection Aim for trough level 10-15nmol / L
Allow a further 2-3 injections after dose adjustment before rechecking
# Available as sachets or pump packs , the latter allowing easier titration . ^ Usually applied to scrotum . * Advantages of a short half-life include faster offset in case of side-effects , and faster recovery of HPT axis if treatment is stopped , with less risk of iatrogenic hypogonadism .
Figure 5 . Application of testosterone gel .
Cardiovascular
Psychological
Gastrointestinal
Growth + development
Figure 6 . Relative energy deficiency in sport .
Immunological
RED-S
Haematological
Menstrual function
Triad
Metabolic
Bone health
Endocrine